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Biomedical subjects

Wallace L M Alward

Publications and source records attributed to Wallace L M Alward.

16 recordsLinked to original sources
PubMed2006

Analysis of RNA splicing defects in PITX2 mutants supports a gene dosage model of Axenfeld-Rieger syndrome.

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is associated with mutations in the PITX2 gene that encodes a homeobox transcription factor. Several intronic PITX2 mutations have been reported in Axenfeld-Rieger patients but their effects on gene expression have not been tested. METHODS: We present two new families with recurrent PITX2 intronic mutations and use PITX2c minigenes and transfected cells to address the hypothesis that intronic mutations effect RNA splicing. Three PITX2 mutations have been analyzed: a G>T mutation within the AG 3' splice site (ss) junction associated with exon 4 (IVS4-1G>T), a G>C mutation at position +5 of the 5' (ss) of exon 4 (IVS4+5G>C), and a previously reported A>G substitution at position -11 of 3'ss of exon 5 (IVS5-11A>G). RESULTS: Mutation IVS4+5G>C showed 71% retention of the intron between exons 4 and 5, and poorly expressed protein. Wild-type protein levels were proportionally expressed from correctly spliced mRNA. The G>T mutation within the exon 4 AG 3'ss junction shifted splicing exclusively to a new AG and resulted in a severely truncated, poorly expressed protein. Finally, the A>G substitution at position -11 of the 3'ss of exon 5 shifted splicing exclusively to a newly created upstream AG and resulted in generation of a protein with a truncated homeodomain. CONCLUSION: This is the first direct evidence to support aberrant RNA splicing as the mechanism underlying the disorder in some patients and suggests that the magnitude of the splicing defect may contribute to the variability of ARS phenotypes, in support of a gene dosage model of Axenfeld-Rieger syndrome.

Abnormalities, Multiple↗
PubMed2006

Retinal synthesis and deposition of complement components induced by ocular hypertension.

Inappropriate activity of the complement cascade contributes to the pathophysiology of several neurodegenerative conditions. This study sought to determine if components of the complement cascade are synthesized in the retina following the development of ocular hypertension (OHT) and if complement accumulates in association with retinal ganglion cells. Toward this goal the gene expression levels of complement components 1qb (C1qb) and 3 (C3) were determined in the retina by quantitative polymerase chain reaction in human eyes with elevated intraocular pressure (IOP) and healthy retinal tissue as well as in a rat model of OHT induced by laser cauterization of the trabecular meshwork and episcleral veins. Immunohistochemical methods were employed to determine the sites of complement deposition in the retina and optic nerve head. Our data demonstrate that transcript levels for C1q and C3 are significantly elevated in retinae subjected to OHT, both in the animal model as well as in human eyes. Immunohistochemical analyses indicate that C1q and C3 accumulate specifically in the retinal ganglion cell layer and the nerve fiber layer. In addition, we demonstrate that the terminal complement complex, or membrane attack complex, is formed both in the human and rat model as a consequence of OHT. Complement activation, particularly formation of membrane attack complexes, has the potential to exacerbate ganglion cell death through bystander lysis or glial cell activation. The results show that complement activation occurs in the retina that has been subjected to elevated IOP, and may have implications in pathophysiology of glaucoma.

Animals↗
PubMed2004

Atypical pigment dispersion syndrome in a child.

PURPOSE: To describe the features of atypical pigment dispersion in a child. DESIGN: Observational case report. METHODS: Retrospective chart review. RESULTS: An 8-year-old boy presented with midperipheral iris transillumination defects, iris backbowing, heavy pigmentation of the trabecular meshwork, and elevated intraocular pressure. He also had several atypical features including emmetropia, mild posterior subcapsular cataract, small pupils, and peripheral anterior synechiae. CONCLUSION: Pigment dispersion in childhood is unusual and may have different features from those classically described in adults.

Cataract↗
PubMed2003

A family with Axenfeld-Rieger syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene.

PURPOSE: Mutations of the forkhead transcription factor gene FOXC1 result in anterior segment anomalies. No description of the spectrum of defects resulting from a single point mutation of this gene exists in the ophthalmology literature. We have screened all available patients with Axenfeld-Rieger genes (PITX2 and FOXC1). In this report, we clinically characterize the spectrum of ocular and systemic manifestations in one family resulting from a previously reported point mutation (Phe112Ser) in FOXC1. DESIGN: Observational case series. METHODS: Ten members of a multigenerational family were examined for signs of glaucoma, anterior segment abnormalities, and systemic features of Axenfeld-Rieger syndrome. The examinations were performed in an ophthalmology examination room or in the patients' homes. Blood was obtained from 10 members and screened for mutations in FOXC1 using direct DNA sequencing. RESULTS: A single mutation causing a T to C change in codon 112 (Phe112Ser) of FOXC1 was present in six members of the family. Five of these six patients were examined and all demonstrated anterior segment anomalies. One patient had Axenfeld anomaly, one had Rieger syndrome, and one had both Axenfeld anomaly and Peters anomaly. Additionally, some members demonstrated cardiac abnormalities, which may be secondary to their FOXC1 mutation. CONCLUSIONS: A wide spectrum of clinical phenotypes can result from a single point mutation of FOXC1. This report confirms that Rieger syndrome (with dental and facial abnormalities) can be caused by a mutation in FOXC1. It is also the first report of Peters anomaly being caused by a FOXC1 mutation.

Abnormalities, Multiple↗
PubMed2003

Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma.

PURPOSE: To investigate the association of sequence variations in the optineurin (OPTN) gene in patients with open-angle glaucoma. DESIGN: Prospective case control study. METHODS: The OPTN gene was screened for sequence variations using a combination of single-strand conformational polymorphism analysis and automated DNA sequencing. A total of 1,299 subjects (1048 glaucoma patients and 251 controls) were screened for variations in the four portions of the gene that had been previously associated with glaucoma. A subset of these subjects (376 patients and 176 controls) was screened for variations in the entire coding sequence. Twenty-four percent of the patients and 35% of the controls were Japanese, whereas the remainder were predominantly Caucasian. Allele frequencies were compared with the Fisher exact test. RESULTS: The OPTN sequence variations were not significantly associated with any form of high-tension open-angle glaucoma. One proband with familial normal-tension glaucoma was found to harbor the previously reported Glu50Lys variation. Another previously reported change, Met98Lys, was associated with normal-tension glaucoma in Japanese but not in Caucasian patients. CONCLUSIONS: This study provides some additional evidence for the association of the Glu50Lys OPTN sequence variation with familial normal tension glaucoma. However, because familial normal-tension glaucoma is so rare, this change seems to be responsible for less than 0.1% of all open-angle glaucoma. The Arg545Gln variation is likely to be a nondisease-causing polymorphism. The Met98Lys change may be associated with a fraction of normal-tension glaucoma in patients of Japanese ethnicity.

Base Sequence↗
PubMed2003

Rate of optic disc cup progression in treated primary open-angle glaucoma.

PURPOSE: To quantitatively evaluate the rate of cup-to-disc ratio progression in treated patients with primary open-angle glaucoma and to identify clinical factors associated with cup progression. PATIENTS AND METHODS: Fifty one eyes of 51 treated primary open-angle glaucoma patients with a minimum of 9-year longitudinal series of stereoscopic optic disc photographs were studied. Eyes with any other ocular disease except for mild cataract were excluded. Each set of stereoscopic photographs was digitized and viewed stereoscopically on a computer screen using a hand-held stereoscope. Computer-aided planimetry was performed on each set of photographs with examiner-defined cup and disc margins using custom-made software. The software computed linear cup-to-disc ratios as well as peripapillary atrophy area. Both inter-observer and intra-observer reliabilities were evaluated in a masked, random fashion using intra-class correlation. Changes in linear cup-to-disc ratios and peripapillary atrophy were estimated using linear regression over time. All available clinical factors were evaluated for association with the rate of cup progression using a multiple regression model. RESULTS: All patients studied were Caucasian; 31(61%) were females. The mean age at the beginning of the study was 61.6 +/- 7.8 years (range 46-81). The mean follow-up period was 14.3 +/- 3.5 years (median 14.0, range 9.6-22.3). A total of 173 sets of stereo disc photographs were analyzed (3.4 +/- 1.3 per patient). The initial and final linear cup-to-disc ratios were 0.64 +/- 0.15 and 0.73 +/- 0.14 respectively. The inter-rater and intra-rater intraclass correlations were 0.76 (95% CI 0.61-0.87) and 0.97 (95% CI 0.93-0.98) respectively. Using linear regression the rate of linear cup-to-disc ratio change was 0.0068 +/- 0.0062 per year (range -0.0025- 0.0269). Three eyes had an increase in the peripapillary atrophy area. The higher yearly average intraocular pressure was significantly associated with faster rate of linear cup-to-disc ratios progression (P = 0.03). CONCLUSIONS: In treated patients with primary open-angle glaucoma, the rate of progressive optic disc cupping was slow (LCDR progression of 0.0068 per year). The higher yearly average intraocular pressure was significantly associated with a faster rate of cup progression.

Aged↗
PubMed2002

Variations in the myocilin gene in patients with open-angle glaucoma.

OBJECTIVE: To determine the prevalence and associated phenotype of myocilin (MYOC) coding sequence variations and a specific promoter polymorphism (MYOC.mt1) in patients with glaucoma and glaucoma suspects. METHODS: A consecutive, unselected series of 779 patients (652 with open-angle glaucoma and 127 glaucoma suspects) were recruited from a university medical center and clinically characterized. The coding sequences of the MYOC gene and the MYOC.mt1 locus in the promoter region were screened for sequence variations. We determined the prevalence of MYOC coding sequence mutations and the MYOC.mt1 promoter polymorphism. We also compared the clinical features of individuals with and without mutations and the MYOC.mt1 promoter polymorphism. RESULTS: Plausible disease-causing sequence variations (DCVs) in the MYOC gene were found in 3.0% of the entire group. Such variations were found in patients with most forms of open-angle glaucoma studied. Patients with primary open-angle glaucoma (POAG) who harbored coding sequence DCVs were clinically similar to patients without them. Patients who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different in any measure of disease severity from those who harbored the more common allele. CONCLUSIONS: MYOC DCVs were found in approximately 3% of patients with glaucoma and glaucoma suspects. The 2 alleles of the MYOC.mt1 promoter polymorphism were equally distributed among patients with POAG and healthy control subjects. Patients with POAG who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different from those with the more common variant in any measure of disease severity. CLINICAL RELEVANCE: Testing for the MYOC.mt1 promoter polymorphism appears to be of no value in the evaluation of patients with glaucoma.

Adult↗
PubMed2002

Progressive axial myopia in a juvenile patient with traumatic glaucoma.

PURPOSE: To report a case of progressive axial myopia associated with traumatic glaucoma in a juvenile patient with no systemic disease. DESIGN: Interventional case report. METHODS: In a 15-year-old male, serial ocular examinations, including manifest refraction, tonometry, and axial eye length measurement, were performed over a 6-year period, beginning with blunt trauma, right eye, followed by a series of surgical procedures for traumatic cataract and glaucoma. RESULTS: A 4-diopter myopic shift (from -1.25 to -5.25) with a 1.5 mm increase in the axial eye length occurred, whereas the intraocular pressure increased from 21 to 46 mm Hg, during a 2-year period. The refraction, axial eye length, and intraocular pressure remained stable during the same period in the fellow, normal eye. CONCLUSION: Progressive axial myopia associated with traumatic glaucoma is possible in a juvenile patient in his late teens.

Adolescent↗
PubMed2002

A case-control comparison of the clinical characteristics of glaucoma and ocular hypertensive patients with and without the myocilin Gln368Stop mutation.

PURPOSE: To determine whether primary open-angle glaucoma (POAG) and ocular hypertensive (OHT) patients who harbor the myocilin Gln368Stop mutation differ in phenotype or clinical course from patients without the mutation. DESIGN: Case-control study. METHODS: A retrospective case-control study compared all known POAG patients (n = 18) and OHT patients (n = 4) harboring the Gln368Stop mutation evaluated by the University of Iowa Glaucoma Service with control patients from the same population. Patients and control subjects were matched for diagnosis, age, sex, and race and were compared for phenotype and clinical course. RESULTS: Mean age of disease onset and mean peak intraocular pressures (IOPs) of cases were similar to those reported by other studies. There was no statistically significant difference between cases and controls for the following variables: age at onset, peak intraocular pressure, Snellen visual acuity, number of medications, Humphrey visual field (HVF) mean deviation, HVF pattern deviation, number of filtering surgeries performed, time intervals from diagnosis to argon laser trabeculoplasty (ALT), diagnosis to first filtering surgery, ALT to first filtering surgery, and percent change in IOP after ALT and after first filtering surgery. CONCLUSIONS: There is no statistically significant difference between the onset and clinical course of POAG and OHT caused by the Gln368Stop mutation and POAG and OHT not associated with the mutation.

Adult↗
PubMed2002

Rate and pattern of visual field decline in primary open-angle glaucoma.

PURPOSE: To study the rate and pattern of visual field decline in primary open-angle glaucoma. DESIGN: Retrospective observational case series. PARTICIPANTS: Forty eyes of 40 patients with primary open-angle glaucoma that were followed longitudinally with serial Goldmann visual fields for a minimum period of 8 years in an academic institution. Eyes with any other ocular disease except for mild cataract were excluded. METHODS: Visual fields obtained with worse than 20/50 Snellen visual acuity from cataract were excluded from analysis. In the remainder (671 Goldmann visual fields), the I4e isopter was quantified manually using a grid template previously described by Esterman. The visual field was divided into central and peripheral, superior and inferior, and nasal and temporal regions, all centered at the blind spot. The rate of visual field decline was estimated for each visual field region (including the four quadrants: superonasal [SN], superotemporal [ST], inferotemporal [IT], and inferonasal [IN]) using linear regression. Asymmetry of visual field progression was determined by comparing the rates of progression among the four quadrants. Pertinent clinical factors were evaluated for association with the asymmetry of visual field progression. MAIN OUTCOME MEASURES: Rates of visual field decline for the entire visual field and each region. Long-term clinical outcome measures, including visual acuity, cataract and cup-to-disc ratio progression, intraocular pressures, and medical and surgical interventions were also studied. RESULTS: The rate of visual field change was -1.3% per year for the entire visual field. The rates of visual field section change (in % per year) were -1.3 (central), -1.4 (peripheral), -1.5 (superior), -1.2 (inferior), -1.4 (nasal), -1.2 (temporal), -1.8 (SN), -1.3 (IT), -1.2 (IN), and -1.1 (ST). About half the patients showed symmetric visual field decline, whereas others showed a more asymmetric pattern. Asymmetric visual field progression was associated with the presence of disc hemorrhage, overall rate of visual field progression, and surgical intervention for glaucoma. CONCLUSIONS: In this group of selected patients with primary open-angle glaucoma with a long-term follow-up, all sections of the visual field declined over time. Disc hemorrhage was associated with more asymmetric visual field progression, implicating focal damage to the optic disc.

Adult↗
PubMed2002

Gonioscopy in primary angle closure glaucoma.

Primary angle closure is a condition characterized by obstruction to aqueous humor outflow by the peripheral iris, and results in changes in the iridocorneal angle that are visible through gonioscopic examination. Gonioscopy in these eyes, however, can be difficult. This chapter discusses techniques that might help in the examination. These include beginning the examination with the inferior angle, methods to help in looking over the iris, cycloplegia, locating the corneal wedge, indentation, van Herick estimation, examining the other eye, and topical glycerin. Finally, there is a discussion about the pathology associated with the closed angle, with emphasis on the appearance of iris bombé, plateau iris, and the distinction between iris processes and peripheral anterior synechiae.

Glaucoma, Angle-Closure↗
PubMedDate not supplied

Myocilin glaucoma.

Genetic factors have long been implicated in the pathophysiology of primary open-angle glaucoma (POAG). Recently, myocilin, a gene of unknown function, was associated with both juvenile open-angle glaucoma (JOAG) and POAG. Forty-three different myocilin mutations have been reported in open-angle glaucoma patients, and several large studies have suggested that as a group these mutations are associated with 3-4% of POAG in patient populations worldwide. Support for the pathogenicity of the individual myocilin mutations has been obtained from in vitro assays, statistical methods, and conservation of gene sequence arguments. Several of these myocilin mutations were observed in multiple patients allowing the identification of mutation-specific glaucoma phenotypes (maximum intraocular pressure and age at diagnosis). Associations between myocilin and other forms of open-angle glaucoma have been explored. At present there is no evidence to link myocilin mutations and steroid-induced ocular hypertension or normal-tension glaucoma. Clinical vignettes of POAG patients from four generations of a family harboring the TYR437HIS myocilin mutation are presented, highlighting the benefits of elucidating the genetics of glaucoma.

Cytoskeletal Proteins↗