Complex genetic mechanisms in glaucoma: An overview.

Glaucomas comprise a group of hereditary optic neuropathies characterized by progressive and irreversible visual field loss and damage to the optic nerve head. It is a complex disease with multiple molecular mechanisms underlying its pathogenesis. Genetic heterogeneity is the hallmark of all glaucomas and multiple chromosomal loci have been linked to the disease, but only a few genes have been characterized, viz. myocilin (MYOC), optineurin (OPTN), WDR36 and neurotrophin-4 (NTF4) in primary open angle glaucoma (POAG) and CYP1B1 and LTBP2 in congenital and developmental glaucomas. Case-control-based association studies on candidate genes involved in different stages of glaucoma pathophysiology have indicated a very limited involvement. The complex mechanisms leading to glaucoma pathogenesis indicate that it could be attributed to multiple genes with varying magnitudes of effect. In this review, we provide an appraisal of the various efforts in unraveling the molecular mystery in glaucoma and also some future directions based on the available scientific knowledge and technological developments.

Genetics and genomics of pseudoexfoliation syndrome/glaucoma

Pseudoexfoliation [PEX] syndrome, one of the most common causes of glaucoma, represents a complex, multifactorial, late-onset disease of worldwide significance. The etiopathogenesis involves both genetic and non-genetic factors. The PEX-specific tissue alterations are caused by a generalized fibrotic matrix process, which has been characterized as a stress-induced elastosis associated with the excessive production and abnormal cross-linking of elastic microfibrils into fibrillar PEX aggregates. The identification of lysyl oxidase-like 1 [LOXL1] as a major genetic risk factor for PEX syndrome and PEX glaucoma further supports a role of elastogenesis and elastosis in the pathophysiology of PEX, as LOXL1 is a pivotal cross-linking enzyme in elastic fiber formation and stabilization. The available data suggest that LOXL1 is markedly dysregulated depending on the stage of the fibrotic process. While transient upregulation of LOXL1 during the early stages of PEX fibrogenesis participates in the formation and aggregation of abnormal PEX fiber deposits, the decreased expression of LOXL1 during the advanced stages of the disease may affect elastin metabolism and promote elastotic processes, e.g. in the lamina cribrosa, predisposing to glaucoma development. However, in view of the low penetrance of the PEX-associated risk variants of LOXL1, other genetic and/or environmental factors must contribute to the risk of developing the PEX phenotype. Some evidence exists for the contribution of additional genes with relatively small effects, e.g. clusterin [CLU], contactin-associated protein-like 2 [CNTNAP2], apolipoprotein E [APOE], glutathione S-transferases [GSTs], and tumor necrosis factor-alpha [TNFA], in certain study populations. Several environmental conditions associated with PEX, such as oxidative stress as well as pro-fibrotic cytokines and growth factors, can regulate expression of LOXL1 and elastic proteins in vitro and may therefore act as co-modulating external factors. Ultimately, both detection and functional characterization of yet unidentified genetic and non-genetic factors may lead to the development of more precise screening tools for the risk of PEX glaucoma

Myocilin mutations are not a major cause of primary congenital glaucoma in Iranian patients

To assess the frequency of mutations in the Myocilin [MYOC] gene in Iranian patients affected with primary congenital glaucoma [PCG]. The individuals evaluated herein are among the larger cohort of 100 patients who had previously been screened for CYP1B1 mutations. Eighty subjects carried mutations in CYP1B1, but the remaining 20 patients who did not, underwent screening for MYOC mutations for the purpose of the study. MYOC exons in the DNA were polymerase chain reaction [PCR] amplified and sequenced. Sequencing was performed using PCR primers, the ABI big dye chemistry and an ABI3730XL instrument. Sequences were analyzed by comparing them to reference MYOC sequences using the Sequencher software. Four MYOC sequence variations were observed among the patients, but none of them were considered to be associated with disease status. Three of these variations were single nucleotide polymorphisms already reported not to be disease causing, the fourth variation created a synonymous codon and did not affect any amino acid change. In this cohort, MYOC mutations were not observed in any Iranian subject with PCG. It is possible that in a larger sample, a few subjects carrying disease causing MYOC mutations could have been observed. But our results show that the contribution of MYOC to PCG status in Iran is small if any

Gene therapy in glaucoma-part I: basic mechanisms and molecular genetics

Glaucoma is the second most common cause of blindness in the world as determined by the World Health Organization [WHO]. Glaucoma diagnosis, identification of people at risk, initiation of treatment and timing of surgical intervention remains a problem. Despite new and improving diagnostic and therapeutic options for glaucoma, blindness from glaucoma remains a major public health problem. The role of heredity in ocular disease is attracting greater attention as knowledge and recent advances of Human Genome Project and the HapMap Project have made genetic analysis of many human disorders possible. Glaucoma offers a variety of potential targets for gene therapy. All risk factors for glaucoma and their underlying causes are potentially susceptible to modulation by gene transfer. The discovery of genes responsible for glaucoma has led to the development of new methods of Deoxyribonucleic acid [DNA]-based diagnosis and treatment. As genetic defects responsible for glaucoma are identified and the biochemical mechanisms underlying the disease are recognized, new methods of therapy can be developed. It is of utmost importance for ophthalmologists and glaucoma specialists to be familiar with and understand the basic molecular mechanisms, genes responsible for glaucoma and the ways of genetic treatment. The literature was searched on the Medline database using the Pubmed interface

Iridotomías con Yag-láser en gemelos heterocigóticos / Yag laser iridotomy applied in heterozygotic twins

Se informa de dos gemelos heterocigóticos de 28 años de edad que al acudir a consulta de oftalmología se les constató un ángulo camerular estrecho, sin hipertensión ocular ni alteraciones de sus campos visuales. Se decidió la realización de iridotomías con láser como prevención de cierre angular intermitente o agudo. Después de realizado este proceder y hasta la actualiadad se ha mantenido un seguimiento sistematico al caso.

This paper reported the case of two heterozygotic twins aged 28 years, who went to the Ophthalmological Service and were diagnosed with a close camerular angle, without suffering either ocular hypertension or visual field alterations. Nd: Yag laser iridotomies was indicated to prevent intermittent or acute angle closure. After this procedure up to the present, this case has been systematically followed-up.

Algunas consideraciones sobre la fisiopatología del glaucoma / Some considerations on the glaucoma physiopathology

Se presentan algunas consideraciones acerca de la fisiopatología del glaucoma. Tradicionalmente se invocaban solo los factores mecánicos y vasculares en la patogenia de esta afección, pero actualmente se conoce que existen otros factores que juegan un importante rol en la neuropatía óptica glaucomatosa, como son los factores genéticos, los factores inmunológicos y los bioquímicos.

Some considerations on the glaucoma physiopathology were presented in this paper. Traditionally, only mechanical and vascular factors were mentioned in the pathogeny of this illness, but it is known at present that there are other factors playing an important role in glaucomatous optic neuropathy such as genetic, immune and biochemical factors.

Investigation of the Association between Normal-tension Glaucoma and Single Nucleotide Polymorphisms in Natriuretic Peptide Gene

PURPOSE: The expression of natriuretic peptides in the neural bundles of the anterior portion of the optic nerves and their functions in regulating vessel tone and blood flow may suggest a possible role in the pathogenesis of glaucoma. The purpose of this study was to investigate the association between normal-tension glaucoma and the genetic variations of atrial natriuretic peptide (Nppa) and natriuretic peptide receptor A (Npr1) gene. METHODS: Sixty-seven Korean normal-tension glaucoma (NTG) patients and 100 healthy subjects (as normal controls) were enrolled. DNA from peripheral blood leukocytes was extracted, and the genotypes of five polymorphisms (c.94G>A, c.454T>C, IVS1+16C>T, IVS2+701G>A, and c.-764C>G) in the Nppa gene and one polymorphism (c.1023G>C) in the Npr1 gene were determined using the restriction fragment length polymorphism and the SNaPshot methods. The genotype and allele frequencies of these polymorphisms in patients with NTG and normal controls were compared using the Fisher's exact test and the chi-square test. RESULTS: In both groups, the genotype distributions were in accordance with the Hardy-Weinberg equilibrium. There was no significant difference in the frequency of the Nppa and Npr1 alleles or genotypes in the normal-tension glaucoma group as compared to the control group. CONCLUSIONS: Nppa and Npr1 gene polymorphisms are not associated with normal-tension glaucoma, suggesting that this gene does not have an important role in the pathogenesis of optic neuropathy in this disease.

Estudo sobre as causas mais freqüentes de perdas oculares / A study on the most frequent causes of ocular losses

As perdas oculares são constrangedoras ao portador por comprometer a face que é parte do corpo humano que possue os órgãos essenciais para o relacionamento humano. Foram avaliados no presente estudo prontuários de 53 pacientes da clínica de prótese buco-maxilo-facial do Centro de Oncologia Bucal da UNESP de Araçatuba, que tiveram a região ocular comprometida, sendo classificadas em ordem de prevalência as causas das perdas oculares. O glaucoma foi responsável por 37 por cento das perdas oculares, seguido por traumas ou acidentes com 32 por cento. Muitas são as causas das perdas oculares, sendo o glaucoma o principal responsável. As próteses oculares foram criadas com o intuito de devolver a função e a estética comprometidas pela ausência de parte ou total do globo ocular

Glaucoma in Costa Rica. Initial approaches: [minireview]

Glaucoma is the second most frequent cause of irreversible blindness worldwide. Genetic factors have been implicated in the development of the disease. So far six loci (GLC1A-GLC1F) and two genes (TIGR/MYOC and OPTN) are involved in the development of juvenile (JOAG) and adult onset or chronic primary open angle glaucoma (COAG), while two loci (GLC3A,GLC3B) and one gene (CYP1B1) are known for primary congenital glaucoma (PCG). Here we summarize the results of the first genetic studies of glaucoma in Costa Rica. Nine families: 1 with JOAG, 1 with PCG and 7 with COAG were screened for mutations at the known genes. A 10 bp duplication, 1546-1555dupTCATGCCACC, at the CYP1B1 gene, causes, in homozygous state, glaucoma in the consanguineous PCG family. This mutation has been found in different countries and generates an early stop codon that termitates protein synthesis 140 amino acids earlier than the normal allele. In exon 1 of the T1GR/MYOC the innocuous Arg76Lys variant was found in two of the COAG families. In the OPTN gene two variants in the coding region (Thr34Thr, Met 98Lys) and 7 intronic changes were found in other Costa Rican glaucoma patients. One of the COAG families was chosen for a genome scan with 379 microsatellite markers and linkage analysis. LOD scores [quot ]suggestive[quot ] of linkage were obtained for several chromosomal regions. Evidence indicates that hereditary glaucoma in Costa Rica is highly heterogeneous and that further studies in the country will probably disclose some up to now unknown genes responsible for the disease.

Neuroprotection in glaucoma.

Currently, glaucoma is recognised as an optic neuropathy. Selective death of retinal ganglion cells (RGC) is the hallmark of glaucoma, which is also associated with structural changes in the optic nerve head. The process of RGC death is thought to be biphasic: a primary injury responsible for initiation of damage that is followed by a slower secondary degeneration related to noxious environment surrounding the degenerating cells. For example, retinal ishaemia may establish a cascade of changes that ultimately result in cell death: hypoxia leads to excitotoxic levels of glutamate, which cause a rise in intra-cellular calcium, which in turn, leads to neuronal death due to apoptosis or necrosis. Neuroprotection is a process that attempts to preserve the cells that were spared during the initial insult, but are still vulnerable to damage. Although not yet available, a neuroprotective agent would be of great use in arresting the progression of glaucoma. There is evidence that neuroprotection can be achieved both pharmacologically and immunologically. Pharmacological intervention aims at neutralising some of the effects of the nerve-derived toxic factors, thereby increasing the ability of the spared neurons to cope with stressful conditions. On the other hand, immunological interventions boost the body's own repair mechanisms for counteracting the toxic effects of various chemicals generated during the cascade. This review, based on a literature search using MEDLINE, focuses on diverse cellular events associated with glaucomatous neurodegeneration, and discusses some pharmacological agents believed to have a neuroprotective role in glaucoma.

Implication of some environmental factors in development of genetic abnormalities associated with some eye disorders in Sharkia, Egypt

A retrospective case-control study was carried out in Sharkia Governorate upon 55 cases with congenital cataract, glaucoma and retinitis pigmentosa and 20 healthy persons as a control group. This study was intended to investigate the mode of inheritance, implication of prenatal environmental exposure and other personal risk factors in development of these serious eye disorders. The subjects were examined according to the following protocol; [1] an interview for recording the relevant personal and family data, [2] complete medical an ophthalmological examinationX3] family pedigree was constructed for each case and, [4] peripheral lymphocyte haryotyping was done for detection of chromosomal abnormalities. The main findings are as follows: [1] the mode of inheritance in primary congenital glaucoma was multifactorial, in congenital cataract as autosmal dominant and recessive and in retinitis pigmentosa it can follow autosomal dominant and recessive, [2] a significant higher prevalence of chromosomal abberration among cases when compared with control, [3] 66.7% of cases with chromosomal abberration had a prenatal history of exposure to some environmental hazards [P<0.01]. [4]; a history of parental exposure to environmental hazards were reported by 2.6% of all cases with congenital eye disorder

Complexo HLA e glaucoma crônico simples / HLA complex and chronic simplex glaucoma

Antígenos HLA-A e B foram determinados em 23 pacientes caucasóides portadores de glaucoma crônico simples. As freqüências antigênicas observadas foram comparadas às obtidas em amostras de populaçäo caucasóide de Säo Paulo. Os resultados obtidos näo revelaram associaçäo com nenhum antígeno HLA-A ou B isoladamente, porém sugeriram associaçäo com os haplotipos HLA-A9B12, A2B40 e A1B8. Estudo de distribuiçäo de haplotipos HLA entre irmäos portadores de glaucoma crônica simples ou de somente pressäo intraocular elevada revelou excesso de haplotipos em comum, sugerindo a presença no complexo HLA, ou próximo ao mesmo, de genes de susceptibilidade a glaucoma crônico simples

Genetic heterogeneity in primary congenital glaucoma

A visäo clássica sobre o mecanismo de herança do Glaucoma Congênito Primário (GCP) é a de que essa anomalia é transmitida de modo autossômico recessivo. Entretanto, a análise de amostras encontradas na literatura, bem como de uma amostra colhida pela autora, mostra que o GCP é, na verdade, uma entidade genética heterogênea, visto que foi possível dectar pelo menos duas formas autossômicas monogênicas dessa doença, sendo uma recessiva e outra dominante. A etiologia do GCP permanece indefinida, porém, em um grande número de casos. Uma investigaçäo aprofundada dessa anomalia sob o ponto de vista genético-clínicoc será necessária tanto para o geneticista quanto para o oftalmologista

Herança no glaucoma congênito / Congenital glaucoma heredity

No presente trabalho foram estudadas 80 famílias, perfazendo um total de 184 filhos, sendo 80 portadores de glaucoma congênito. As famílias foram divididas segundo o número de filhos de cada casal e procurou-se verificar em qual dos filhos, segundo a ordem de nascimento, incidiu o glaucoma congênito. Concluiu-se que tais estudos säo pouco informativos. No entanto, entre outros achados, foi observado que o glaucoma congênito ocorreu no primeiro filho em näo mais do que 47,5% dos casos e que a ocorrência da doença em mais de uma vez numa mesma família é esporádica e até certo ponto rara

Glaucoma congênito: relaçäo entre idade, estadio evolutivo e resultado cirúrgico / Congenital glaucoma: relationship among age, stage of evolution and surgical results

Foi realizado um estudo retrospectivo de pacientes portadores de glaucoma congênito, que compareceram à Clínica Oftalmológica da Santa Casa de Misericórdia de Säo Paulo, entre maio de 1981 e dezembro de 1986. Os pacientes foram classificados em, 3 estadios evolutivos, conforme o grau de alteraçöes anatômicas, provocadas pela doença. Relacionou-se idade e grau de evoluçäo no primeiro atendimento com resultado cirúrgico. Ocorreu uma diferença nítida clínicamente entre as idades e os resultados cirúrgicos obtidos, diferença essa estatísticamente näo significativa pelo método estatístico empregado, provavelmente, devida à escassez amostral

Autosomal recessive anterior chamber dysgenesis

Descreve-se o caso de dois irmäos portadores de disgenesia da câmara anterior do olho associada a glaucoma, cujos genitores eram normais e consangüíneos. Um raro padräo de herança autossômico recessivo parece ser o mais provável neste caso