To investigate which clinical measures influence whether an individual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fiber layer (pRNFL) or macular ganglion ...cell-inner plexiform layer (mGCIPL).
Prospective, longitudinal cohort study.
Two hundred seventy-one eyes from 207 individuals with statistically significant evidence of glaucomatous progression on OCT Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 individuals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance.
Individuals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared with individuals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis.
Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL.
Intraocular pressure, baseline pRNFL thickness, baseline mGCIPL thickness, and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pretreatment IOP (mean difference, 3.90 mmHg; 95% confidence interval CI, 2.37-5.43 mmHg; P < 0.001). The interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5-mmHg increase in IOP (95% CI, 10.32-15.72 months). Eyes demonstrating earliest longitudinal progression on mGCIPL showed significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference, 7.07 μm; 95% CI, 4.38-9.77 μm; P < 0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to demonstrate a new paracentral field defect than eyes progressing first on pRNFL parameters (odds ratio, 3.03; 95% CI, 1.26-7.28; P = 0.01).
Clinical features, particularly pretreatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the usefulness of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.
Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and ...identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10
) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
IMPORTANCE: Nanophthalmos is a congenital disorder characterized by small eyes, with the main complications being severe hyperopia and angle-closure glaucoma. OBJECTIVE: To perform a clinical and ...genetic investigation of a large white family with autosomal dominant nanophthalmos. DESIGN, SETTING, AND PARTICIPANTS: Detailed clinical evaluation and a genome-wide linkage scan was conducted in the family NNO-SA1. Linkage was evaluated with a 10K single-nucleotide polymorphism array, followed by whole exome sequencing, to identify novel segregating coding variants within the linked region. The candidate gene was screened for mutations in additional independent families by direct sequencing of the coding exons and intron/exon boundaries. The expression pattern of the candidate gene in ocular tissues was analyzed by reverse transcriptase–polymerase chain reaction. Participants were recruited through ophthalmology clinics at Flinders Medical Centre, Adelaide, South Australia, Australia. Nanophthalmos was defined as an axial length less than 20.0 mm and/or refractive error greater than +7.00. Of the 35 available individuals from family NNO-SA1, 16 participants (46%) had a diagnosis of nanophthalmos, with mean refraction of +11.8 D and mean axial length of 17.6 mm. Unaffected unrelated individuals serving as controls were screened for the identified mutation. Additional independent families with clinically diagnosed nanophthalmos were also recruited. MAIN OUTCOMES AND MEASURES: Nanophthalmos status. RESULTS: Significant linkage was detected on chromosome 17 between single-nucleotide polymorphism markers rs2323659 and rs967293, with a maximum location score of 4.1. Exome sequencing identified a single novel segregating missense variant within the linkage region located in exon 8 of the transmembrane-98 (TMEM98) gene c.577G>C (p.Ala193Pro), which was absent in the Exome Variant Server database and among 285 local white individuals serving as controls. The TMEM98 gene was expressed in all ocular tissues tested including sclera and optic nerve head. CONCLUSIONS AND RELEVANCE: A novel gene associated with nanophthalmos, TMEM98 most likely represents the cause of the disease in this family. To our knowledge, this represents the first gene identified causing autosomal dominant nanophthalmos.
Phototherapeutic keratectomy (PTK) with 193-nm excimer laser is a safe and effective procedure for the treatment of superficial corneal pathology. We aimed to review the use of PTK for the treatment ...of corneal macular dystrophy (MCD).
Case report and literature review.
A 16-year-old boy presented to an ophthalmologist with a 4-year history of reduced vision, glare and photophobia in his left eye. He was diagnosed with corneal macular dystrophy and underwent sequencing of the CHST6 gene. Left excimer PTK with mitomycin C was performed. He remained relapse free until 18 months post procedure when his visual acuity declined and the stroma appeared more "milky". He underwent a penetrating keratoplasty in his left eye 24 month following the initial PTK.
Phototherapeutic keratectomy is an effective means of visual restoration in patients with macular corneal dystrophy and may delay penetrating keratoplasty. Patients should be counselled regarding the high risk of recurrence. This is the first reported case of a CHST6 gene positive patient with MCD that was treated with phototherapeutic keratoplasty.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Axenfeld-Rieger syndrome encompasses a group of developmental disorders affecting the anterior chamber structures of the eye, with associated systemic features in some cases. This study aims to ...compare the difference in anterior segment phenotypes such as those involving the cornea, iris, lens, and anterior chamber angle between cases with disease-causing sequence variations in FOXC1 and PITX2 .
This cross-sectional study involved 61 individuals, from 32 families with pathogenic FOXC1 or PITX2 variants, who were registered with the Australian and New Zealand Registry of Advanced Glaucoma.
The median age of the cohort was 39 years at the time of last assessment (range 3-85 years; females, 54%). Thirty-two patients had pathogenic variants in the FOXC1 gene, and 29 patients had pathogenic variants in the PITX2 gene. Corneal abnormalities were more common in individuals with FOXC1 variants (18/36, 50%) than those with PITX2 variants (4/25, 16%; P = 0.007). Iris abnormalities such as hypoplasia ( P = 0.008) and pseudopolycoria ( P = 0.001) were more common in individuals with PITX2 variants than those with FOXC1 variants. Glaucoma was present in 72% of participants. Corneal decompensation was positively associated with corneal abnormalities ( P < 0.001), glaucoma surgery ( P = 0.025), and cataract surgery ( P = 0.002).
Corneal abnormalities were more common in individuals with FOXC1 than in those with PITX2 variants and were often associated with early onset glaucoma. These findings highlight that patients with FOXC1 variations require close follow-up and monitoring throughout infancy and into adulthood.
IMPORTANCE: Both primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of ...secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma. OBJECTIVE: To investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma. DESIGN, SETTING, AND PARTICIPANTS: Australian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l’Azienda Socio–Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017. MAIN OUTCOME AND MEASURES: Identification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them. RESULTS: A total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome. CONCLUSIONS AND RELEVANCE: These data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.
IMPORTANCE: The p.Gln368Ter (rs74315329) risk allele in the myocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were ...recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom. OBJECTIVES: To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT). DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018. MAIN OUTCOMES AND MEASURES: The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT. RESULTS: A total of 411 337 UKBB participants of white British ancestry (mean SD age, 56.6 8.0 years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%. CONCLUSIONS AND RELEVANCE: The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.
Gelsolin (GSN) variants have been implicated in amyloidosis of the Finnish type. This case series reports a novel GSN:c.1477T>C,p.(Trp493Arg) variant in a family with ocular and systemic features ...consistent with Finnish Amyloidosis. Exome sequencing performed on affected individuals from two families manifesting cutis laxa and polymorphic corneal stromal opacities demonstrated the classic GSN:c.654G>A,p.Asp214Asn variant in single affected individual from one family, and a previously undocumented GSN:c.1477T>C variant in three affected first‐degree relatives from a separate family. Immunohistochemical studies on corneal tissue from a proband with the c.1477T>C variant identified gelsolin protein within histologically defined corneal amyloid deposits. This study reports a novel association between the predicted pathogenic GSN:c.1477T>C variant and amyloidosis of the Finnish type, and is the first to provide functional evidence of a pathological GSN variant at a locus distant to the critical G2 calcium‐binding region, resulting in the phenotype of amyloidosis of the Finnish type.
Corneal opacities in an individual harboring the novel pathogenic GSN:c1477T>C variant
To investigate and report on the quality-of-life (QoL) issues experienced by caregivers of individuals with childhood glaucoma.
Exploratory, qualitative study.
Thirty-five caregivers of individuals ...with childhood glaucoma (defined as disease onset before 18 years of age) recruited from the Australian and New Zealand Registry of Advanced Glaucoma.
A qualitative research methodology (interpretive phenomenology) was applied. Data were collected through semistructured in-depth interviews. NVivo-12 software (QSR International Pty Ltd) was used to analyze, code, and organize data into QoL themes inductively.
Quality-of-life themes and their subthemes.
The mean caregiver age was 50.2 ± 13.6 years, and 27 of 35 caregivers (77%) were mothers of an individual with childhood glaucoma. A total of 6 QoL themes were identified. Coping strategies and emotional well-being were the most prominent themes. Caregivers frequently adopted problem-focused adaptive coping strategies including partner or peer support, and normalization. A caregiver’s psychosocial well-being was often impacted by feelings of guilt and regret regarding their child’s delayed diagnosis, fear and anxiety related to medical and social support, and loss of control as their child developed medical autonomy. The effect of family planning from the perspective of the caregiver formed a novel QoL theme and was associated with normalization and parental confidence in management of the condition.
Childhood glaucoma poses a substantial threat to a caregiver’s psychosocial well-being. Strategies that promote normalization, peer support, psychotherapeutic intervention, and genetic counseling may be indicated and, indeed, critical to the caregiver as they adapt to supporting their child with glaucoma.
Purpose To investigate the presence of TBK1 copy number variations in a large, well-characterized Australian cohort of patients with glaucoma comprising both normal-tension glaucoma and high-tension ...glaucoma cases. Design A retrospective cohort study. Methods DNA samples from patients with normal-tension glaucoma and high-tension glaucoma and unaffected controls were screened for TBK1 copy number variations using real-time quantitative polymerase chain reaction. Samples with additional copies of the TBK1 gene were further tested using custom comparative genomic hybridization arrays. Results Four out of 334 normal-tension glaucoma cases (1.2%) were found to carry TBK1 copy number variations using quantitative polymerase chain reaction. One extra dose of the TBK1 gene (duplication) was detected in 3 normal-tension glaucoma patients, while 2 extra doses of the gene (triplication) were detected in a fourth normal-tension glaucoma patient. The results were further confirmed by custom comparative genomic hybridization arrays. Further, the TBK1 copy number variation segregated with normal-tension glaucoma in the family members of the probands, showing an autosomal dominant pattern of inheritance. No TBK1 copy number variations were detected in 1045 Australian patients with high-tension glaucoma or in 254 unaffected controls. Conclusion We report the presence of TBK1 copy number variations in our Australian normal-tension glaucoma cohort, including the first example of more than 1 extra copy of this gene in glaucoma patients (gene triplication). These results confirm TBK1 to be an important cause of normal-tension glaucoma, but do not suggest common involvement in high-tension glaucoma.
PDF
