RESUMEN
PURPOSE: To compare stage of visual field loss (VFL) and age at diagnosis between patients with different types of glaucoma with regard to glaucoma screening and driving ability. METHODS: In a cross-sectional study of 1988 consecutive patients with different types of glaucoma VFL at diagnosis and age at diagnosis were assessed. Patients with binocular advanced or severe VFL were classified unable, patients with no VFL in one eye and VFL I-V (Aulhorn classification) in the other eye able, all other constellations questionably able to drive. RESULTS: There were significant differences in age at diagnosis between different glaucomas and between patients with different stages of VFL at diagnosis. Age-related assessment of VFL at diagnosis in normal tension glaucoma (NTG) compared to primary open-angle glaucoma (POAG) showed that NTG is not a disease of the elderly but a disease with late diagnosis at severe VFL. In POAG a solely age-related glaucoma screening, e.g. from the age of 50 years, does not sufficiently lead to diagnosis at an early stage of the disease. In POAG solely based on binocular VFL 11.5% of patients were judged unable, 29.2% questionably able to drive, in NTG 19.6%/43.1%, pigmentary glaucoma 16%/22%, pseudoexfoliation glaucoma 9.1%/16.7%, and in primary angle-closure glaucoma 14.6%/30%. CONCLUSIONS: Depending on type of glaucoma more than 50% of patients require counselling regarding safe driving as part of clinical care. A disease-specific, age-related perimetric examination considering additional risk factors like family history of glaucoma is essential for early detection of glaucoma and road safety.
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Conducción de Automóvil , Glaucoma/diagnóstico , Tamizaje Masivo/métodos , Campos Visuales/fisiología , Adulto , Edad de Inicio , Anciano , Estudios Transversales , Femenino , Glaucoma/fisiopatología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total Nâ=â1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
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Estudio de Asociación del Genoma Completo , Glaucoma de Ángulo Abierto/genética , Presión Intraocular/genética , Proteínas del Tejido Nervioso/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cuerpo Ciliar/metabolismo , Cuerpo Ciliar/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nervio Óptico/metabolismo , Nervio Óptico/patología , Polimorfismo de Nucleótido Simple , Malla Trabecular/metabolismo , Malla Trabecular/patologíaRESUMEN
The molecular events responsible for obstruction of aqueous humor outflow and the loss of retinal ganglion cells in glaucoma, one of the main causes of blindness worldwide, remain poorly understood. We identified a synonymous variant, c.765C>T (Thr255Thr), in ankyrin repeats and suppressor of cytokine signaling box-containing protein 10 (ASB10) in a large family with primary open angle glaucoma (POAG) mapping to the GLC1F locus. This variant affects an exon splice enhancer site and alters mRNA splicing in lymphoblasts of affected family members. Systematic sequence analysis in two POAG patient groups (195 US and 977 German) and their respective controls (85 and 376) lead to the identification of 26 amino acid changes in 70 patients (70 of 1172; 6.0%) compared with 9 in 13 controls (13 of 461; 2.8%; P = 0.008). Molecular modeling suggests that these missense variants change ASB10 net charge or destabilize ankyrin repeats. ASB10 mRNA and protein were found to be strongly expressed in trabecular meshwork, retinal ganglion cells and ciliary body. Silencing of ASB10 transcripts in perfused anterior segment organ culture reduced outflow facility by â¼50% compared with control-infected anterior segments (P = 0.02). In conclusion, genetic and molecular analyses provide evidence for ASB10 as a glaucoma-causing gene.
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Empalme Alternativo , Glaucoma de Ángulo Abierto/genética , Mutación Missense/genética , Proteínas Supresoras de la Señalización de Citocinas/genética , Malla Trabecular/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Repetición de Anquirina , Secuencia de Bases , Estudios de Casos y Controles , Células Cultivadas , Cuerpo Ciliar/citología , Cuerpo Ciliar/metabolismo , Femenino , Glaucoma de Ángulo Abierto/patología , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Técnicas de Cultivo de Órganos , Linaje , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/química , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Malla Trabecular/metabolismo , Adulto JovenRESUMEN
Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Predisposición Genética a la Enfermedad/genética , Glaucoma de Ángulo Abierto/genética , Proteínas de Homeodominio/genética , Disco Óptico/metabolismo , Estudios de Cohortes , Glaucoma de Ángulo Abierto/metabolismo , Humanos , Modelos Logísticos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Glaucoma, a main cause of blindness in the developed world, is characterized by progressive degeneration of retinal ganglion cells (RGCs), resulting in irreversible loss of vision. Although members of the neurotrophin gene family in various species are known to support the survival of numerous neuronal populations, including RGCs, it is less clear whether they are also required for survival and maintenance of adult neurons in humans. Here, we report seven different heterozygous mutations in the Neurotrophin-4 (NTF4) gene accounting for about 1.7% of primary open-angle glaucoma patients of European origin. Molecular modeling predicted a decreased affinity of neurotrophin 4 protein (NT-4) mutants with its specific tyrosine kinase receptor B (TrkB). Expression of recombinant NT-4 carrying the most frequent mutation was demonstrated to lead to decreased activation of TrkB. These findings suggest a pathway in the pathophysiology of glaucoma through loss of neurotrophic function and may eventually open the possibility of using ligands activating TrkB to prevent the progression of the disease.
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Glaucoma de Ángulo Abierto/genética , Glaucoma de Ángulo Abierto/patología , Mutación , Factores de Crecimiento Nervioso/genética , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Neuronas/metabolismo , Receptor trkB/genética , Transducción de SeñalRESUMEN
PURPOSE: To identify the underlying genetic cause in a two generation German family diagnosed with isolated aniridia. METHODS: All patients underwent full ophthalmic examination. Mutation screening of the paired box gene 6 (PAX6) was performed by bidirectional Sanger sequencing. A minigene assay was applied to analyze transcript processing of mutant and wildtype PAX6 variants in HEK293 cells. RESULTS: We identified a PAX6 sequence variant at the splice donor site (+5) of intron 12. This variant has been described before in another family with aniridia but has not been characterized at the transcript level. We could demonstrate that the mutant allele causes the skipping of exon 12 during transcript processing. The mutation is predicted to result in a 'run on' translation past the normal translational stop codon. CONCLUSIONS: A splice site mutation resulting in exon skipping was found in a family with autosomal dominant aniridia. The mutation is predicted to result in an enlarged protein with an extra COOH-terminal domain. This very likely affects the transactivation properties of the PAX6 protein.
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Aniridia/genética , Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Amaurosis Congénita de Leber/genética , Mutación Missense , Factores de Transcripción Paired Box/genética , Sitios de Empalme de ARN/genética , Proteínas Represoras/genética , Población Blanca/genética , Secuencia de Bases , Exones , Femenino , Genes Dominantes , Alemania , Células HEK293 , Heterocigoto , Humanos , Intrones , Masculino , Datos de Secuencia Molecular , Factor de Transcripción PAX6 , Linaje , Análisis de Secuencia de ADN , TransfecciónRESUMEN
BACKGROUND: Various lines of evidence demonstrate the involvement of mitochondrial dysfunction in the pathogenesis of glaucoma. Therefore, mitochondrial DNA is a promising candidate for genetic susceptibility studies on glaucoma. To test the hypothesis that mitochondrial haplogroups influence the risk to develop glaucoma, we genotyped 12 single-nucleotide polymorphisms that define the European mitochondrial DNA haplogroups in healthy controls and two German patient cohorts with either exfoliation glaucoma or the normal tension subgroup of primary open angle glaucoma. RESULTS: Mitochondrial haplogroup U was significantly under-represented in patients with exfoliation glaucoma (8.3% compared with 18.9% in controls; p = 0.004). CONCLUSIONS: People with haplogroup U have a lower risk to develop exfoliation glaucoma. Our results substantiate the suggestion that mitochondrial alterations have an impact on the etiology of glaucoma.
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ADN Mitocondrial/genética , Síndrome de Exfoliación/genética , Población Blanca/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Alemania , Glaucoma de Ángulo Abierto/genética , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Reports on open globe injuries caused by exploding bottles containing carbonated drinks have already raised the demand to switch from multi-use glass bottles to plastic bottles. We retrospectively analyzed our files to find out whether this type of injury is limited to multi-use glass bottles, and to what extent carelessness contributed to the injury PATIENTS: Among 1,402 open globe injuries that were treated in the departments of ophthalmology at the universities of Freiburg and Würzburg between 1981 and 2004, we retrospectively identified 33 injuries caused by exploding bottles containing carbonated drinks. Patients were excluded from analysis when the destruction of the bottle was intended (destroyed with a hammer, or bottle used as a weapon). The circumstances of the injury, the treatment and the functional outcome was analyzed. RESULTS: 2.4% of all open globe injuries were related to exploding bottles, with a risk of one injury per 1 million inhabitants per year. Ten eyes suffered from a spontaneous explosion of the bottle when it was moved on a shelf or taken out of a box. Eighteen eyes received the injury after the bottle had fallen down and exploded (six of them in children 2 to 8 years). Five bottles exploded during opening of the bottle. In four cases, the bottle cap came off spontaneously and penetrated the eye. Eleven injuries (33%) occurred at work, five of them while moving the bottle and six during breaks at work. CONCLUSION: Spontaneous explosions in multi-use glass bottles could easily be avoided by changing to plastic bottles; however, exploding single-use glass bottles Containing sparkling wine also contributed to the injuries. In many cases, carelessness was involved. Glass bottles should be never exposed to heat or shaking, and children should never carry glass bottles containing carbonated drinks.
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Traumatismos por Explosión/etiología , Bebidas Gaseosas , Lesiones Oculares Penetrantes/etiología , Embalaje de Alimentos/instrumentación , Vidrio , Adolescente , Adulto , Distribución por Edad , Anciano , Traumatismos por Explosión/epidemiología , Traumatismos por Explosión/cirugía , Niño , Preescolar , Explosiones , Lesiones Oculares Penetrantes/epidemiología , Lesiones Oculares Penetrantes/cirugía , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Oftalmológicos , Estudios Retrospectivos , Rotura , Estaciones del Año , Distribución por Sexo , Agudeza Visual/fisiologíaRESUMEN
BACKGROUND: Normal tension glaucoma is a major subtype of glaucoma, associated with intraocular pressures that are within the statistically normal range of the population. Monogenic forms following classical inheritance patterns are rare in this glaucoma subtype. Instead, multigenic inheritance is proposed for the majority of cases. The present study tested common sequence variants in candidate genes for association with normal tension glaucoma in the German population. METHODS: Ninety-eight SNPs were selected to tag the common genetic variation in nine genes, namely OPTN (optineurin), RDX (radixin), SNX16 (sorting nexin 16), OPA1 (optic atrophy 1), MFN1 (mitofusin 1), MFN2 (mitofusin 2), PARL (presenilin associated, rhomboid-like), SOD2 (superoxide dismutase 2, mitochondrial) and CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1). These SNPs were genotyped in 285 cases and 282 fully evaluated matched controls. Statistical analyses comprised single polymorphism association as well as haplogroup based association testing. RESULTS: Results suggested that genetic variation in five of the candidate genes (RDX, SNX16, OPA1, SOD2 and CYP1B1) is unlikely to confer major risk to develop normal tension glaucoma in the German population. In contrast, we observed a trend towards association of single SNPs in OPTN, MFN1, MFN2 and PARL. The SNPs of OPTN, MFN2 and PARL were further analysed by multimarker haplotype-based association testing. We identified a risk haplotype being more frequent in patients and a vice versa situation for the complementary protective haplotype in each of the three genes. CONCLUSION: Common variants of OPTN, PARL, MFN1 and MFN2 should be analysed in other cohorts to confirm their involvement in normal tension glaucoma.
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Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad , Glaucoma de Ángulo Abierto/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: To compare visual field loss (VFL) in eyes with optic nerve head drusen (ONHD) with or without ocular hypertension (OHT). METHODS: The records of all patients aged 45 years or older with a diagnosis of ONHD at 2 centers were reviewed. OHT was defined as intraocular pressure >or=22 mm Hg. We categorized ONHD into 3 grades based on visibility on disc photographs. RESULTS: We identified 22 eyes (13 patients) with both ONHD and OHT and 81 normotensive eyes (47 patients) with ONHD. VFL was present in 20/22 (90.9%) of hypertensive eyes compared with 54/81 (66.7%) of normotensive eyes (P=0.03, Fisher exact test). Drusen grade III and OHT were both independently and significantly associated with greater incidence of VFL (logistic regression analysis). CONCLUSIONS: VFL occurs more frequently in eyes with ONHD that also have OHT. Eyes with grade III ONHD are at increased risk for VFL compared to eyes with grade I drusen with the same intraocular pressure status. Patients with OHT and ONHD should undergo close surveillance for disease progression and be treated appropriately to prevent additional VFL.
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Hipertensión Ocular/complicaciones , Drusas del Disco Óptico/complicaciones , Trastornos de la Visión/complicaciones , Campos Visuales , Femenino , Humanos , Presión Intraocular , Masculino , Persona de Mediana Edad , Hipertensión Ocular/diagnóstico , Hipertensión Ocular/fisiopatología , Drusas del Disco Óptico/diagnóstico por imagen , Drusas del Disco Óptico/fisiopatología , Ultrasonografía , Trastornos de la Visión/diagnóstico , Trastornos de la Visión/fisiopatología , Pruebas del Campo VisualRESUMEN
PURPOSE: To determine the prevalence of WDR36 sequence variants in a cohort of German patients with normal tension glaucoma. METHODS: All of the 23 coding exons and flanking introns of the WDR36 gene were amplified by PCR from genomic DNA and subjected to denaturing high performance liquid chromatography. Samples with aberrant profiles were sequenced. In addition, restriction fragment length polymorphism analysis was performed in order to identify previously described nucleotide changes. RESULTS: This study identified 11 nucleotide changes in the WDR36 gene that lead to predicted amino acid substitutions. Previously reported disease-causing mutations were found in 4% of patients (4/112) whereas sequence variants previously classified as disease-susceptibility mutations were found in 5% of patients (6/112). One nonsynonymous nucleotide change that has not been reported before was found in one patient. Mutation screening also identified several exonic and intronic polymorphisms. CONCLUSIONS: The findings in the current study indicate that WDR36 gene variants may be only rare causes of normal tension glaucoma in the German population.
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Proteínas del Ojo/genética , Variación Genética , Glaucoma/fisiopatología , Presión Intraocular , Población Blanca/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Secuencia de Bases , Estudios de Cohortes , Exones , Femenino , Predisposición Genética a la Enfermedad , Alemania , Glaucoma/genética , Glaucoma de Ángulo Abierto/genética , Humanos , Intrones , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
PURPOSE: Prospective evaluation of family history (FH) of glaucoma and FH of optic disc drusen (ODD) in patients with sonographically confirmed ODD. PATIENTS AND METHODS: A total of 87 patients with ODD interviewed all their first-degree and second-degree relatives using a detailed questionnaire on whether an ophthalmologist had diagnosed or excluded glaucoma or ocular hypertension (OH). Using a second questionnaire, 62 of these patients also provided information about ODD in their FH. Control groups for FH of glaucoma consisted of 2170 patients with glaucoma or OH evaluated with the same methods and identical questions for FH of glaucoma in a previous study, and of 176 healthy individuals without glaucoma or ODD who were interviewed on family history of glaucoma. RESULTS: Glaucoma in FH was significantly more frequent in patients with ODD with an incidence of 20.7% compared with healthy controls with an incidence of 2.8%, and half as frequent as in glaucoma patients with an incidence of 40%. ODD in FH were found in 9.7% of patients with ODD. CONCLUSIONS: As there is a high frequency of family history of glaucoma in patients with ODD, evaluation of FH of ODD and FH of glaucoma is essential in patients with ODD. Glaucoma in FH of ODD patients requires intraocular pressure monitoring and whenever deemed beneficial timely initiation of intraocular pressure-lowering therapy.
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Glaucoma/epidemiología , Drusas del Disco Óptico/epidemiología , Adulto , Femenino , Glaucoma/fisiopatología , Humanos , Incidencia , Presión Intraocular , Masculino , Persona de Mediana Edad , Hipertensión Ocular/fisiopatología , Estudios Prospectivos , Encuestas y Cuestionarios , Tonometría OcularRESUMEN
PURPOSE: To determine the prevalence of FOXC1 and PITX2 mutations and to assess clinical phenotypes in a cohort of German patients with Axenfeld-Rieger malformations. METHODS: All coding exons of the FOXC1 and PITX2 genes were amplified by PCR from genomic DNA and subjected to direct DNA sequencing. Analysis of mutations in control subjects was performed by restriction fragment length polymorphism (RFLP) analysis. RESULTS: Sequence variants were identified by DNA sequencing in 15 of 19 cases. Mutation screening identified four potentially pathogenic FOXC1 mutations causing amino acid substitutions (P79R, Y115S, G149D, and M161V) that were not present in 100 control subjects. In addition, two different 1-bp deletions causing a frameshift and subsequent premature stop codon were identified in two subjects. One patient harbored a FOXC1 nonsense mutation (S48X). Mutation screening also identified two potentially pathogenic PITX2 mutations (P64L and P64R) in two index patients that were excluded in 100 healthy control subjects. CONCLUSIONS: The findings in the present study clearly demonstrate that FOXC1 and PITX2 mutations are responsible for a significant proportion of Axenfeld-Rieger malformations in Germany.
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Segmento Anterior del Ojo/anomalías , Anomalías del Ojo/genética , Factores de Transcripción Forkhead/genética , Glaucoma/genética , Proteínas de Homeodominio/genética , Iris/anomalías , Mutación , Factores de Transcripción/genética , Secuencia de Aminoácidos , Codón/genética , Análisis Mutacional de ADN , Femenino , Humanos , Presión Intraocular/genética , Masculino , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Análisis de Secuencia de ADN , Proteína del Homeodomínio PITX2RESUMEN
PURPOSE: To determine the prevalence of optineurin (OPTN) and myocilin (MYOC) sequence variants in a cohort of German patients with normal tension glaucoma. METHODS: All coding exons of the OPTN and MYOC genes were amplified by PCR from genomic DNA and subjected to direct DNA sequencing. Analysis of sequence variants in controls was done by denaturing high performance liquid chromatography (DHPLC) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: Sequence variants were identified by DNA sequencing in 10 of 112 cases. The OPTN sequence variant M98K was found in seven patients. In addition, two novel sequence variants (A336G and A377T) in the OPTN gene were identified that were not present in a control group. Mutation screening also identified two potentially pathogenic MYOC mutations (T293K and A445V). CONCLUSIONS: The findings in the current study provide further evidence that MYOC and OPTN gene variants are rare causes of NTG.
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Proteínas del Citoesqueleto/genética , Proteínas del Ojo/genética , Variación Genética , Glaucoma de Ángulo Abierto/genética , Glicoproteínas/genética , Factor de Transcripción TFIIIA/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Ciclo Celular , Cromatografía Líquida de Alta Presión , Femenino , Alemania/epidemiología , Glaucoma de Ángulo Abierto/etnología , Humanos , Intrones/genética , Masculino , Proteínas de Transporte de Membrana , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Prevalencia , Análisis de Secuencia de ADN , Regiones no Traducidas/genéticaRESUMEN
PURPOSE: To evaluate frequency of migraine, vasospasm (VS), family history (FH) of migraine, and family history of glaucoma (FHG) in different types of glaucoma in relation to age and stage of visual field loss (VFL) at diagnosis. METHODS: A total of 2170 patients with glaucoma or ocular hypertension (OH) were interviewed by using standardized questions concerning FHG, age at diagnosis, and potential risk factors, including migraine and VS. Of 2027 patients providing information on migraine, 1244 had primary open-angle glaucoma (POAG), 140 normal tension glaucoma (NTG), 49 pigmentary glaucoma, 64 pseudoexfoliation glaucoma (PEX), 138 OH, and 218 primary angle closure glaucoma (PACG). RESULTS: Of all patients, 13.7% reported migraine, 19.0% VS, 30.8% FH of migraine, and 40.3% FHG. Patients with FHG had a significantly higher frequency of migraine than patients without FHG (15.7% vs. 12.3%, P = 0.02). Migraine was significantly more frequent in NTG (21.4%) than POAG (13.1%; P = 0.01), PEX (7.8%; P = 0.02), and PACG (10.1%; P = 0.004). Compared to patients with POAG, patients with NTG had a 63.5% higher age-corrected probability for migraine (P = 0.007). There was no evidence for migraine or VS being prognostic factors regarding the extent of VFL at diagnosis. Migraine and VS were significantly more frequent in females. CONCLUSIONS: The higher frequency of migraine and VS in females could contribute to the female preponderance in NTG. Our findings suggest an association of NTG and migraine and a common, possibly polygenetic, vascular etiology of these two diseases both with familial predisposition.
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Glaucoma/etiología , Trastornos Migrañosos/complicaciones , Hipertensión Ocular/etiología , Vasoespasmo Intracraneal/complicaciones , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Factores Sexuales , Trastornos de la Visión/etiología , Campos Visuales/fisiologíaRESUMEN
PURPOSE: To evaluate in different types of glaucoma frequency of family history of glaucoma (FHG), age at diagnosis, glaucoma risk in relatives, and acceptance rate of genetic glaucoma tests. To assess stage of visual field loss (VFL) in relation to FHG. METHODS: Using standardized questions whether an ophthalmologist had found or excluded glaucoma or ocular hypertension (OH), 2170 patients with glaucoma or OH interviewed all their first and second degree relatives. One thousand three hundred thirty-eight patients had POAG, 233 primary angle closure glaucoma (PACG), 148 OH, 153 normal tension glaucoma (NTG), 50 pigmentary glaucoma (PG), and 66 pseudoexfoliation glaucoma (PEX). RESULTS: Frequency of FHG was 40% in POAG, without significant differences compared with NTG (P = 0.08), OH (P = 0.5), PACG (P = 0.4), and PG (P = 0.6). There were significant differences in age at diagnosis between the glaucomas (smallest between group P < 0.0001). Patients with FHG were significantly younger at diagnosis than patients without FHG in all types of glaucoma (all P values ≤ 0.03), except NTG and PEX. Patients' siblings and mothers had the highest detection probability for glaucoma in POAG and OH. There was no significant relation between stage of VFL and FHG in POAG (P = 0.6). Sixty-eight percent of patients would participate in genetic glaucoma tests. CONCLUSIONS: There is a similarly high genetic disposition in all types of glaucoma. Disease risk was especially high in mothers and siblings. In patients with FHG, knowledge of genetic disposition of the glaucomas may have led to earlier diagnosis. This highlights the need for glaucoma awareness campaigns.
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Predisposición Genética a la Enfermedad , Glaucoma/epidemiología , Tamizaje Masivo , Vigilancia de la Población/métodos , Adulto , Anciano , Femenino , Alemania/epidemiología , Glaucoma/genética , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
PURPOSE: To evaluate the following in patients with aniridia: age at first examination at the University Eye Hospital and age at diagnosis of glaucoma; visual acuity; frequency of family history of aniridia; and frequency of ocular and general diseases associated with aniridia. METHODS: This was a consecutive examination of 30 unrelated patients with aniridia and retrospective evaluation of ophthalmologic, pediatric, and internal findings. The relative frequency of age at glaucoma diagnosis within decades was evaluated for the 20 patients with aniridia and glaucoma. Statistical analysis was performed using the Mann-Whitney test. RESULTS: Relative frequency of the age of patients with aniridia at time of glaucoma diagnosis within the following decades was as follows: from birth to 9 years: 15%, 10-19: 15%, 20-29: 15%, 30-39: 15%, 40-49: 35%, and 50-59: 5%. Visual acuity in the better eye of 20/100 or less was found in 60%. Family history of aniridia was found in 33.3% of patients, with 1-4 relatives with aniridia. A total of 76.7% of patients had congenital cataract, and 66.7% had glaucoma. Mean maximum intraocular pressure of the 20 patients with glaucoma was 35.9 mmHg in the right and 32.6 mmHg in the left eye. A total of 53.3% had nystagmus, 26.6% corneal opacifications, 16.7% bilateral lens dislocation upwards, 6.7% optic nerve hypoplasia, 3.3% poor foveal development, and 3.3% Wilms tumor. CONCLUSIONS: Up to the age of 40 years, 15% of patients were diagnosed with glaucoma per age decade. Frequent bilateral glaucoma and similar bilateral height of intraocular pressure suggest a genetic glaucoma disposition with malformation at Schlemm canal, besides possible sequential anatomic changes in the chamber angle. Associated ocular abnormalities limit visual prognosis.
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Aniridia/epidemiología , Oftalmopatías/epidemiología , Glaucoma/epidemiología , Neoplasias Renales/epidemiología , Tumor de Wilms/epidemiología , Adolescente , Adulto , Distribución por Edad , Edad de Inicio , Anciano , Aniridia/genética , Niño , Preescolar , Oftalmopatías/diagnóstico , Oftalmopatías/genética , Proteínas del Ojo/genética , Alemania/epidemiología , Glaucoma/diagnóstico , Glaucoma/genética , Gonioscopía , Proteínas de Homeodominio/genética , Humanos , Lactante , Presión Intraocular/fisiología , Neoplasias Renales/genética , Persona de Mediana Edad , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box/genética , Proteínas Represoras/genética , Estudios Retrospectivos , Tonometría Ocular , Agudeza Visual/fisiología , Tumor de Wilms/genética , Adulto JovenRESUMEN
Glaucoma is a genetically heterogeneous disorder and is the second cause of blindness worldwide owing to the progressive degeneration of retinal ganglion neurons. Very few genes causing glaucoma were identified to this date. In this study, we screened 10 candidate genes of glaucoma between the D14S261 and D14S121 markers of chromosome 14q11, a critical region previously linked to primary open-angle glaucoma (POAG). Mutation analyses of two large cohorts of patients with POAG, normal tension glaucoma (NTG) and juvenile open-angle glaucoma (JOAG), and control subjects, found only association of non-synonymous heterozygous variants of the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) with POAG, NTG and JOAG. The 20 non-synonymous variants identified in RPGRIP1 were all distinct from variants causing photoreceptor dystrophies and were found throughout all but one domain (RPGR-interacting domain) of RPGRIP1. Among them, 14 missense variants clustered within or around the C2 domains of RPGRIP1. Yeast two-hybrid analyses of a subset of the missense mutations within the C2 domains of RPGRIP1 shows that five of them (p.R598Q, p.A635G, p.T806I, p.A837G and p.I838V) decrease the association of the C2 domains with nephrocystin-4 (NPHPH). When considering only these five confirmed C2-domain mutations, the association remains statistically significant (P=0.001). Altogether, the data support that heterozygous non-synonymous variants of RPGRIP1 may cause or increase the susceptibility to various forms of glaucoma and that among other factors, physical impairment of the interaction of RPGRIP1with different proteins may contribute to the pathogenesis of forms of glaucoma.
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Glaucoma de Ángulo Abierto/genética , Glaucoma de Baja Tensión/genética , Proteínas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ceguera/genética , Proteínas del Citoesqueleto , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Heterocigoto , Humanos , Presión Intraocular , Masculino , Persona de Mediana Edad , Mutación Missense , Retinitis Pigmentosa/genética , Factores de Riesgo , Adulto JovenRESUMEN
Genetic and nongenetic factors contribute to development of pseudoexfoliation (PEX) syndrome, a complex, age-related, generalized matrix process frequently associated with glaucoma. To identify specific genetic variants underlying its etiology, we performed a genome-wide association study (GWAS) using a DNA-pooling approach. Therefore, equimolar amounts of DNA samples of 80 subjects with PEX syndrome, 80 with PEX glaucoma (PEXG) and 80 controls were combined into separate pools and hybridized to 500K SNP arrays (Affymetrix). Array probe intensity data were analyzed and visualized with expressly developed software tools GPFrontend and GPGraphics in combination with GenePool software. For replication, independent German cohorts of 610 unrelated patients with PEX/PEXG and 364 controls as well as Italian cohorts of 249 patients and 190 controls were used. Of 19, 17 SNPs showing significant allele frequency difference in DNA pools were confirmed by individual genotyping. Further single genotyping at CNTNAP2 locus revealed association between PEX/PEXG for two SNPs, which was confirmed in an independent German but not the Italian cohort. Both SNPs remained significant in the combined German cohorts even after Bonferroni correction (rs2107856: P(c)=0.0108, rs2141388: P(c)=0.0072). CNTNAP2 was found to be ubiquitously expressed in all human ocular tissues, particularly in retina, and localized to cell membranes of epithelial, endothelial, smooth muscle, glial and neuronal cells. Confirming efficiency of GWAS with DNA-pooling approach by detection of the known LOXL1 locus, our study data show evidence for association of CNTNAP2 with PEX syndrome and PEXG in German patients.
Asunto(s)
Síndrome de Exfoliación/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , ADN/genética , ADN/aislamiento & purificación , Femenino , Frecuencia de los Genes , Alemania , Humanos , Inmunohistoquímica , Masculino , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Programas Informáticos , Población Blanca/genéticaRESUMEN
Axenfeld-Rieger syndrome (ARS) (OMIM Nr.: 180500) is a rare autosomal dominant disorder (1 : 200000) with genetic and morphologic variability. Glaucoma is associated in 50% of the patients. Craniofacial and dental anomalies are frequently reported with ARS. The present study was designed as a multidisciplinary analysis of orthodontic, ophthalmologic, and genotypical features. A three-generation pedigree was ascertained through a family with ARS. Clinically, radiographic and genetic analyses were performed. Despite an identical genotype in all patients, the phenotype varies in expressivity of craniofacial and dental morphology. Screening for PITX2 and FOXC1 mutations by direct DNA-sequencing revealed a P64L missense mutation in PITX2 in all family members, supporting earlier reports that PITX2 is an essential factor in morphogenesis of teeth and craniofacial skeleton. Despite the fact that the family members had identical mutations, morphologic differences were evident. The concomitant occurrence of rare dental and craniofacial anomalies may be early diagnostic indications of ARS. Early detection of ARS and elevated intraocular pressure (IOP) helps to prevent visual field loss.