Glaucoma can be inherited as a mendelian autosomal-dominant or autosomal- recessive trait, or as a complex multifactorial trait. Genetic approaches have. Primary Congenital Glaucoma (Infantile Glaucoma). 3-year-old female referred for evaluation of increased eye size, OS. Presented by Jeffrey. Glaucoma is a group of eye diseases which result in damage to the optic nerve and vision loss. The most common type is open-angle glaucoma with less.

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Genetic Etiologies of Glaucoma. Copyright American Medical Association. Glaucoma can be inherited as a mendelian autosomal-dominant or autosomal-recessive trait, or as a complex multifactorial trait. Genetic approaches have helped define the underlying molecular events responsible for some mendelian forms of the disease and have identified the chromosome locations of genes that are likely to contribute to common complex forms.

Future directions include the discovery of new glaucoma genes, determining the clinical phenotypes associated with specific genes and mutations, investigating environmental factors that may contribute to the disease, investigating gene-environment interactions and gene-gene interactions, and developing a mutation database that can be used for diagnostic and prognostic testing.

Glaucoma is the third most prevalent cause of visual impairment and blindness among white Americans and is the leading cause of blindness among black Americans. In most instances, the elevation of IOP results from impaired drainage glajcoma aqueous humor produced by the ciliary body through the trabecular meshwork outflow pathways.

Glaucoma causes irreversible blindness that can only be prevented by therapeutic intervention at early stages of the disease. A family history of the disease has long been recognized as a major risk factor for glaucoma, suggesting that specific gene defects contribute to the pathogenesis of the disorder. The identification of the molecular events responsible for glaucoma has been difficult because of a general lack of knowledge about the cellular and biochemical events that are necessary for congenuto normal regulation of IOP and retinal ganglion congenuto function.

Access to diseased human tissue is also difficult and animal models have only recently been developed and characterized.

The identification of comgenito and their protein glauvoma that can cause or contribute to glaucoma will help define the underlying pathophysiology, as well as lead to the development of new DNA-based diagnostic tests and novel therapeutic approaches.

The availability of predictive tests would provide a mechanism for early detection and treatment. Those individuals at risk who are identified early in the course of the disease and who begin therapy prior to significant damage to the optic nerve will have the best chance of maintaining useful sight.

Genes associated with forms of glaucoma that exhibit autosomal-dominant, autosomal-recessive, and other mendelian inheritance patterns can be located in the human genome using large affected pedigrees typically at least 11 members and standard linkage analysis.

Once the chromosomal location of the gene is determined, the genes found within the linkage region can be evaluated for association with the disease. The simplicity of this overall approach has lead to substantial success and most of the genes currently glaucoa to be associated glaucpma various forms of glaucoma were identified using these methods Table.

Common forms of adult-onset glaucoma, including primary open-angle glaucoma POAGtypically do not exhibit mendelian inheritance patterns.

These common age-related ocular disorders do glauocma a significant heritability; however, the genetic contributions to these disorders are complex, resulting from interactions of multiple genetic factors, and are susceptible to the influence of environmental exposures.

Discovering genes that contribute to disorders with complex inheritance is more difficult. Among the factors that contribute to the challenge of discovering complex disease genes are the underlying molecular heterogeneity, imprecise definition of phenotypes, inadequately powered study designs, vongenito the inability of standard sets of microsatellite markers to extract complete information about inheritance.

Genome scans using families demonstrating clustering of complex diseases largely sibpairs typically lead to the identification of a number of large genetic intervals containing many possible candidate genes. This approach has been successful in the identification of some ocular disease genes 7 – conyenito ; however, most of the identified genes do not appear to have a major role in the complex phenotype.

Typically, early-onset forms of glaucoma are inherited as mendelian-dominant or mendelian-recessive traits, including early-onset open-angle glaucoma 19 – 23 ; congenital glaucoma 24 ; development glaucomas, including Rieger syndrome, 25 – 28 glaucoma associated with nail-patella syndrome, 29 and nanophthalmos 30 glauvoma and glaucoma associated with pigment dispersion syndrome.

In patients with congenital glaucoma, the development of the anterior segment of the eye and aqueous humor outflow pathways is abnormal, causing high IOP. Congenital glaucoma can be inherited as an autosomal-recessive trait and is prevalent in countries where consanguinity is common.

Subsequently, mutations in this gene have also been found in patients with congenital glaucoma from many countries including Slovakia gypsies and Japan, and from countries with more heterogeneous populations, such as the United States and Brazil.

A loss of protein function is probably the underlying genetic mechanism, as most of the mutations are deletions, insertions, or missense mutations occurring in highly conserved protein regions that are necessary vongenito its function. Congentio work indicates the recurrent mutations are on ancient chromosomes that have a common haplotype. It has been hypothesized that alterations glaucoms the metabolism of estrogens may be the basis for the ocular abnormalities associated with defects in this gene.


Most patients with congenital glaucoma caused by mutations in CYP1B1 have a severe case of the disease; however, there are some families with significant variation in phenotypic severity and even reduced penetrance, which is evident from the observation of apparently unaffected homozygote carriers.

In addition to congenital glaucoma, other forms of glaucoma are associated with abnormal development of the anterior segment of the eye. Axenfeld-Rieger syndrome, characterized by posterior embryotoxon, iris hypoplasia, and iridocorneal adhesions, can be caused by mutations in the PITX2 gene. Abnormalities in the PAX6 gene cause aniridia, as well as a spectrum of iris conggenito related to glaucoma.

The genes responsible for these disorders participate in the regulation of gene expression during development, 53 – 55 specifically in the development of the congeniito mesenchyme, congwnito includes neural crest— and cranial paraxial mesoderm—derived cells.

Intrafamilial variability in disease severity is commonly encountered in pedigrees carrying defects in these genes. The variable phenotypic expressivity may be caused by dosage effects or by gkaucoma coexistence of other genes that can modify the expression of the trait. In patients with both early- and late-onset disease, the majority of congenlto causative mutations are found in the olfactomedin domain of the protein, which is encoded by sequences found in the third exon of the gene. Although the clustering of glaucoma-associated mutations in the olfactomedin domain and the participation of olfactomedins in extra- cellular processes suggests that the myocilin protein functions in the extracellular matrix, the role of the normal protein in the outflow pathways is not well understood.

Several studies suggest that myocilin is not needed for normal aqueous humor outflow. It is likely that mutant forms congenuto the myocilin protein have an abnormal function that may result in retention of the abnormal form of the protein in the cell. Disease-causing myocilin mutants appear to be misfolded and are highly aggregation prone, causing large-protein aggregates to accumulate in the endoplasmic reticulum.

Secretion of mutant myocilin has been shown to be temperature sensitive, which supports the hypothesis that myocilin-induced glaucoma is a protein-conformational disease. Further studies will be required to glauccoma the actual mechanism of myocilin-associated glaucoma. For a number of glaucoma-associated genes, the chromosomal location of the gene has been determined by linkage studies. The gene has yet to be identified. Linkage studies and chromosome-deletion analyses suggest that genes responsible for anterior segment developmental abnormalities are located on chromosomes 13q14, 28 4p, 74 16q, 75 and 20p.

In humans the disease can be sporadic or inherited, with most pedigrees demonstrating autosomal-dominant inheritance patterns. Neither of these genes contribute to the disease in humans.

Nanophthalmos can dongenito inherited as an autosomal-recessive or autosomal-dominant trait, and vlaucoma patients are at risk for angle-closure glaucoma. One gene, MFRP membrane-type Frizzled-related proteinlocated on glaucomw 11q23, has been shown to be associated with autosomal-recessive nanopthlamos.

Adult-onset forms of glaucoma, including POAG, low-tension glaucoma, and glaucoma associated with pseudoexfoliation, are inherited as complex glaucomz. A positive family history is a major risk factor for these conditions, which suggests that congfnito gene defects are likely to contribute.

It is more likely that multiple genes contribute to these phenotypes and that environmental conditions may also participate. Because a genetic model cannot be defined, methods to identify genes responsible for these conditions are more complex than glaucona used for mendelian disorders. Genome scans and model-free analyses have been performed using families demonstrating clustering of complex diseases largely sibpairsas well as families affected with rare forms showing apparent mendelian inheritance.

In patients with low-tension glaucoma, degeneration of the optic nerve occurs even though the IOPs are not abnormally elevated. In patients with low-tension glaucoma, the clinical appearance of the optic nerve is similar to the appearance of the optic nerve in the Kjer form of autosomal-dominant optic atrophy. Loss of function mutations in the OPA1 gene are responsible for Kjer autosomal-dominant optic atrophy; polymorphisms cojgenito the OPA1 gene may be associated with low-tension glaucoma in glauco,a cases.

Low-tension glaucoma has also been associated with mutations in a novel gene, OPTN. Missense mutation in optineurin is an infrequent cause of low-tension glaucoma, with a possible increase in prevalence in the Japanese population.

Studies of lymphocytes in patients with low-tension glaucoma have demonstrated altered expression of the p53 gene, a known regulator of apoptosis. Although not true for optineurin, the possibility remains that genes that predispose patients to low-tension glaucoma may also contribute to nerve degeneration in patients with POAG associated with increased IOP. Primary glauvoma glaucoma commonly occurs after age 50 years and is usually associated with elevated IOP.

The relationship between pressure elevation and optic nerve disease is not linear, suggesting that variability in optic nerve susceptibility exists among glaucoma patients. Adult-onset glaucoma often occurs in multiple family members familial aggregation but does not usually follow a clear mendelian inheritance pattern, suggesting that inherited risk factors can result in a susceptibility to the disease but alone are not necessarily causative. Using mendelian model-dependent linkage approaches and small numbers of large pedigrees affected by POAG, 7 genetic loci have been described for POAG GLC1A-G21, – and glaucoma-predisposing genes have been identified in 3 of these loci: Genomic studies using model-free linkage analysis complex disease gene approaches have identified the chromosome locations of adult-onset POAG susceptibility genes.


Congenital Glaucoma Campaign – Luah – Barcelona – Glaucoma Congénito – Luah – Barcelona

Using mainly white US sibling pairs affected by POAG, 7 genomic regions were identified, 6 and recent follow-up information on this population demonstrates additional evidence for POAG-susceptibility loci on chromosomes 14q11 locus pending J. Single nucleotide polymorphism—based approaches are proving successful for complex diseases, 14 – 18 and the application of these technologies to adult-onset POAG is the focus of current studies.

Although a linkage study has not yet been completed for pseudoexfoliation glaucoma, systemic abnormalities, including gglaucoma of homocysteine, have been identified in affected patients.

Inherited disorders of the optic nerve include degenerative processes primarily glaucoma, as described previouslyas well as primary disorders causing optic nerve atrophy. Leber hereditary optic neuropathy is caused by missense mutations in mitochondrial DNA, while Kjer autosomal-dominant optic atrophy is caused by mutations in the OPA1 gene. The clinical features that define glaucoma phenotypes associated with specific mutations genotypes must be established before useful clinical information can be acquired from DNA-based diagnostic testing.

For the genes that have been identified as responsible for glaucoma, or associated with glaucoma, clinical information about the onset of disease, course of disease, and response to therapy needs to be collected.

As new genes glaucomw for different forms of inherited glaucoma are discovered, clinical disease features should be correlated with specific mutations. These genotype-phenotype studies will include the answers to the following questions: Such mutations would require other additional genetic defects or environmental factors to be fully manifest.

The development of genotype-phenotype databases for glaucoma genes and mutations will be an important step toward clinically useful DNA-based diagnostic testing for glaucoma. Genetic factors are at least in part responsible for all forms of glaucoma, with the exception of glaucoma related to trauma and infection.

Currently, the genetic origins of the majority of glaucoma cases are unknown, as the known genes account for only a small fraction of heritable cases. With the advent of single glaucomz polymorphism—based technologies, it is likely that a number of genes responsible for glaucoma will be identified in the next 5 years.

Genes that contribute to glaucoma may influence elevation of IOP or susceptibility to optic nerve degeneration, or both. It is highly likely, glaaucoma in any complex disease, that complex forms of glaucoma, such as adult-onset POAG, result not only from the independent actions of multiple genes but also from the interaction of multiple genes epistasis. For late-onset diseases it is likely that the genetically determined disease features are more sensitive to environmental influences because of disruption of normal physiologic homeostatic mechanisms.

Genetic Etiologies of Glaucoma

Currently, little is known about environmental factors that may influence the onset or progression of congehito POAG. Recent studies suggest that factors congeinto to glaucoma metabolism and type II diabetes mellitus may increase the risk of glaucoma.

One of the goals of disease gene discovery is the development of predictive congenifo tests. For a disease such as glaucoma, where early treatment can be beneficial, diagnostic tests designed to identify individuals at risk for the disease can be particularly valuable.

Current testing for glaucoma genes is limited to genes that are known to be associated with glaucoma and is primarily diagnostic, rather than prognostic. Except for specific mutations in the MYOC and OPTN genes, details regarding the predicted clinical course associated with a glaucoma gene mutation cannot be provided.

Genotype-phenotype studies as outlined earlier will help define the prognostic aspects of currently known glaucoma gene mutations.

: Infantile Glaucoma, Congenital Glaucoma

Ultimately the goal is to discover a complete panel of genes that contribute to glaucoma and develop diagnostic and prognostic correlates for the mutations found in each gene. Such a panel would provide a mechanism to identify individuals at risk for the disease and initiate timely treatment before irreversible optic nerve degeneration and blindness occurs.

August 4, ; final revision received September 24, ; accepted September 26, Download PDF Top of Article Abstract Genetic approaches Genes associated with forms of glaucoma with mendelian inheritance New genes associated with mendelian forms of glaucoma supported by linkage studies Genes associated with forms of glaucoma with complex inheritance Adult-Onset POAG New genes associated with complex forms of glaucoma supported by linkage studies Genes associated with primary optic neuropathies Future directions Article Information References.

Prevalence of open-angle glaucoma among adults in the United States. Meta-analysis of genome scans of age-related macular degeneration. Genomewide linkage scan for myopia susceptibility loci among Ashkenazi Jewish families show evidence of linkage on chromosome 22q