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D A Mackey

Publications and source records attributed to D A Mackey.

At least 37 records · Page 2Linked to original sources
PubMed2001

A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye.

Mutations in the forkhead transcription-factor gene (FOXC1), have been shown to cause defects of the anterior chamber of the eye that are associated with developmental forms of glaucoma. Discovery of these mutations was greatly facilitated by the cloning and characterization of the 6p25 breakpoint in a patient with both congenital glaucoma and a balanced-translocation event involving chromosomes 6 and 13. Here we describe the identification of novel mutations in the FOXC1 gene in patients with anterior-chamber defects of the eye. We have detected nine new mutations (eight of which are novel) in the FOXC1 gene in patients with anterior-chamber eye defects. Of these mutations, five frameshift mutations predict loss of the forkhead domain, as a result of premature termination of translation. Of particular interest is the fact that two families have a duplication of 6p25, involving the FOXC1 gene. These data suggest that both FOXC1 haploinsufficiency and increased gene dosage can cause anterior-chamber defects of the eye.

Anterior Chamber↗
PubMed2001

The Taa1 restriction enzyme provides a simple means to identify the Q368STOP mutation of the myocilin gene in primary open angle glaucoma.

PURPOSE: To identify a rapid and reliable method to detect the Glutamine 368 STOP (Q368STOP) disease-predisposing allele of the myocilin gene associated with adult onset, primary, open-angle glaucoma. METHODS: Individuals with the Q368STOP mutation of the myocilin gene were identified from a cohort of primary open-angle glaucoma patients from Tasmania and subjected to Taa1 restriction digestion. RESULTS: In the Tasmanian family presented, screening with the Taa1 restriction enzyme successfully confirmed identification of all individuals with the Q368STOP mutation. CONCLUSIONS: The use of the Taa1 restriction enzyme offers a relatively simple, rapid, and reproducible technique that could be applied to detect the Q368STOP mutation of the myocilin gene.

Codon, Terminator↗
PubMed2001

Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier.

OBJECTIVE: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP). DESIGN: Cross-sectional genetic study. PARTICIPANTS: Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. METHODS: Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS: From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 +/- 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 +/- 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals the mean age at diagnosis was higher (62.3 +/- 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 +/- 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. CONCLUSIONS: The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.

Adult↗
PubMed2001

Laboratory methods in ophthalmic genetics: obtaining DNA from patients.

DNA samples are the fundamental research substrate in genetics. Although methodology and cost-effectiveness in molecular biology have improved dramatically, collecting biological samples and extracting DNA continue to be expensive and time-consuming steps of genetic research. This article reviews the issues surrounding the choice of biological samples for methods of DNA extraction as well as the storage and transport of biological and DNA samples for genetic studies.

DNA↗
PubMed2001

Visual improvement despite radiologically stable disease after treatment with carboplatin in children with progressive low-grade optic/thalamic gliomas.

BACKGROUND: The purpose of this study was to examine the clinical and radiologic response to carboplatin by children with progressive optic/thalamic gliomas. PATIENTS AND METHODS: Between July 1997 and July 1999, 12 consecutive children were treated with monthly carboplatin for progressive optic/thalamic gliomas. RESULTS: Five children have completed 12 cycles of carboplatin and five children are currently receiving treatment. Two children had progressive disease noted both clinically and radiologically. Nine children have stable radiologic disease and one child has had a partial radiologic response to chemotherapy. Eight children have had regular visual assessments. Four children (three with stable radiology and one with a partial radiologic response) have had improvement in their vision. Three children with radiologically stable disease have had no change in vision. One child has had deterioration in vision despite radiologically stable disease. CONCLUSIONS: The results suggest that the clinical response of optic/thalamic gliomas to carboplatin, as measured by visual acuity and visual fields, may be better than predicted by radiologic assessment. These data suggest that a prospective clinical study is warranted of the role of carboplatin in children with progressive optic/thalamic gliomas and visual impairment.

Adolescent↗
PubMed2001

Evaluation of the myocilin (MYOC) glaucoma gene in monkey and human steroid-induced ocular hypertension.

PURPOSE: Glucocorticoid-induced ocular hypertension (the steroid response) may result in optic nerve damage that very closely mimics the pathologic course of primary open angle glaucoma (POAG). In addition, patients with glaucoma and their relatives are much more likely to exhibit the steroid response than unaffected individuals, suggesting a potential link between the steroid response and POAG. Recently, the expression of a gene (MYOC) in the trabecular meshwork was shown to be steroid-induced. MYOC variations thought to be disease-causing also were found in 3% to 5% of POAG cases. The purpose of this study was to determine whether some variations in MYOC might be involved in steroid-induced ocular hypertension. METHODS: Seventy human steroid responders and 114 control subjects were screened for variations in the coding sequence and promoter of MYOC. Also, topical doses of dexamethasone (DEX) were administered to cynomolgus monkeys to determine their steroid responsiveness, and the MYOC orthologue was cloned from the cynomolgus monkey. RESULTS: Overall, 109 instances of 20 different sequence variations were identified in the human myocilin gene. However, only four of these (each observed in a single individual) met the study criteria for a possible phenotype-altering variation. Three of these were present in steroid responders and one in a control patient, a distribution that was not statistically significant (P: = 0.3). In addition, the allele frequency of a closely flanking marker was compared between the steroid responders and the control subjects, and no evidence for linkage disequilibrium was observed. Reproducible and reversible ocular hypertension was induced in approximately 40% of the monkeys treated with DEX, similar to that seen in man. Ten monkeys were screened for MYOC mutations with single-strand conformation polymorphism (SSCP) analysis. Overall, 37 instances of 13 different sequence variations were observed. Four of these changes met the study criteria for a possible phenotype-altering variation, and these were equally distributed between responder and nonresponder monkeys. CONCLUSIONS: This study identified no statistically significant evidence for a link between MYOC mutations and steroid-induced ocular hypertension.

Administration, Topical↗
PubMed2000

Vigabatrin-associated visual field defects in children.

PURPOSE: Vigabatrin (Sabril), a drug that blocks GABA transaminase, has been used in the treatment of epilepsy since 1989. There have been reports of irreversible constriction of the visual field in adult patients related to vigabatrin (VGB) therapy, resulting in reduced VGB usage in adults. Although used as a second or third line agent in adults, in children it is often considered as a first line treatment for several subgroups of seizures in spite of there being no way, in the majority of cases, to monitor visual fields. Some of these children have a pre-existing visual field defect as part of their primary disorder. We aimed to identify whether visual field loss due to VGB was occurring in our hospital. METHODS: We have studied the results of ophthalmic examination in 14 children on VGB at Great Ormond Street Hospital who were able to perform Goldmann visual fields. RESULTS: Ten of the 14 patients had constriction of their visual fields attributed to VGB. In addition there were 2 patients with suspicious visual field defects thought to be due to VGB. There was pre-existing visual pathway damage in 4 cases and in 2 of these optic disc pallor increased in association with constricted visual fields. However, the optic discs were normal in 7 patients in spite of visual field constriction. Visual acuity was generally normal in spite of gross visual field constriction. CONCLUSIONS: We believe that VGB should be used with great caution where there is pre-existing visual pathway damage. In other cases the benefits should be considered in relation to the risks, which include irreversible visual field damage. At present visual fields can only be monitored by perimetry, which is often not possible in children with epilepsy.

Adolescent↗
PubMed2000

Accuracy and implications of a reported family history of glaucoma: experience from the Glaucoma Inheritance Study in Tasmania.

OBJECTIVES: To ascertain the prevalence of previously undiagnosed primary open-angle glaucoma (POAG) within 5 large POAG pedigrees and to evaluate the reliability of a reported family history of glaucoma within these pedigrees. METHODS: The Glaucoma Inheritance Study in Tasmania (GIST) identified several large adult POAG pedigrees. Intraocular pressure (IOP), optic disc stereophotography, and automated perimetry were performed on all adult pedigree members. Participants were classified as normal (IOP <22 mm Hg and normal optic disc and field); glaucoma suspect (normal field, but an IOP >/=22 mm Hg and/or suspicious optic disc); or POAG (field defect and glaucomatous optic disc). Some individuals with POAG had been previously diagnosed by their local ophthalmologist; others were diagnosed as a result of the GIST project. Family members with a prior diagnosis of POAG were asked to report if they were aware of any relatives with POAG. This reported family history was then directly compared with the actual pedigree (before the diagnosis of new cases) to calculate agreement. MAIN OUTCOME MEASURE: The rate of glaucoma in pedigrees and percentage of previously diagnosed glaucoma cases who were aware of the positive family history of POAG. RESULTS: Four hundred forty-two subjects (mean age, 54 years [range, 13-97 years]) from 5 pedigrees were examined: 316 subjects (71%) were normal, 47 (11%) were previously diagnosed with POAG, and 8 (2%) were previously diagnosed glaucoma suspects; 30 cases (7%) of POAG and 41 suspects (9%) were newly diagnosed as a direct result of the GIST examination. Of the 47 previously diagnosed POAG cases, 41 were questioned about their prior knowledge of any family history and 11 (27%) were unaware of their family history of POAG. CONCLUSIONS: Examination of all adult subjects from POAG families yields new cases. Even in large POAG pedigrees, 27% of previously diagnosed POAG patients were unaware of their positive family history. These findings suggest that a higher percentage of adult POAG may be inherited than hitherto reported. Arch Ophthalmol. 2000;118:900-904

Adolescent↗
PubMed1999

Inhaled corticosteroids, family history, and risk of glaucoma.

OBJECTIVE: Until recently, inhaled corticosteroids were not considered to cause elevated intraocular pressure (IOP), although topical and oral corticosteroids have been shown to do so in susceptible individuals. The authors aimed to (1) identify whether an association existed between inhaled corticosteroid use and elevated IOP or open-angle glaucoma and (2) determine whether this effect may have a genetic basis. DESIGN: Cross-sectional, population-based study of 3654 persons 49 to 97 years of age attending the Blue Mountains Eye Study, near Sydney, Australia. METHODS: A series of questions assessed use of inhaled and other corticosteroids as well as family history of glaucoma. Elevated IOP was assessed using applanation tonometry. Diagnosis of glaucoma was based on automated perimetry defects and optic disc signs but without reference to IOP. MAIN OUTCOME MEASURE: Statistical analysis of associations between inhaled corticosteroid use and elevated IOP or glaucoma, by family history, adjusting for other risk factors. RESULTS: Open-angle glaucoma was diagnosed in 108 subjects, and elevated IOP was found in 160 subjects. In persons with a glaucoma family history, there was a strong association between inhaled corticosteroid use and presence of either glaucoma or elevated IOP (odds ratio [OR], 2.6; 95% confidence interval, 1.2-5.8). The risk increased with higher doses (OR, 6.3; 95% CI, 1.0-38.6) for persons who used more than four puffs per day. These findings were not explained by concurrent use of oral or ocular corticosteroids. In persons without a family history of glaucoma, no association was found between use of inhaled corticosteroids and glaucoma or elevated IOP. CONCLUSIONS: These findings suggest an association between ever use of inhaled corticosteroids and a finding of elevated IOP or glaucoma in subjects with a glaucoma family history. Patients being treated with inhaled corticosteroids need review by an ophthalmologist if they report a glaucoma family history.

Administration, Inhalation↗
PubMed1999

A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy.

Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD) refer to two autosomal dominant diseases characterized by yellow-white deposits known as drusen that accumulate beneath the retinal pigment epithelium (RPE). Both loci were mapped to chromosome 2p16-21 (refs 5,6) and this genetic interval has been subsequently narrowed. The importance of these diseases is due in large part to their close phenotypic similarity to age-related macular degeneration (AMD), a disorder with a strong genetic component that accounts for approximately 50% of registered blindness in the Western world. Just as in ML and DHRD, the early hallmark of AMD is the presence of drusen. Here we use a combination of positional and candidate gene methods to identify a single non-conservative mutation (Arg345Trp) in the gene EFEMP1 (for EGF-containing fibrillin-like extracellular matrix protein 1) in all families studied. This change was not present in 477 control individuals or in 494 patients with age-related macular degeneration. Identification of this mutation may aid in the development of an animal model for drusen, as well as in the identification of other genes involved in human macular degeneration.

Aging↗
PubMed1999

Analysis of myocilin mutations in 1703 glaucoma patients from five different populations.

A glaucoma locus, GLC1A, was identified previously on chromosome 1q. A gene within this locus (encoding the protein myocilin) subsequently was shown to harbor mutations in 2-4% of primary open angle glaucoma patients. A total of 1703 patients was screened from five different populations representing three racial groups. There were 1284 patients from primarily Caucasian populations in Iowa (727), Australia (390) and Canada (167). A group of 312 African American patients was from New York City and 107 Asian patients from Japan. Overall, 61 different myocilin sequence variations were identified. Of the 61 variations, 21 were judged to be probable disease-causing mutations. The number of probands found to harbor such mutations in each population was: Iowa 31/727 (4.3%), African Americans from New York City 8/312 (2.6%), Japan 3/107 (2.8%), Canada 5/167 (3.0%), Australia 11/390 (2.8%) and overall 58/1703 (3. 4%). Overall, 16 (76%) of 21 mutations were found in only one population. The most common mutation observed, Gln368Stop, was found in 27/1703 (1.6%) glaucoma probands and was found at least once in all groups except the Japanese. Studies of genetic markers flanking the myocilin gene suggest that most cases of the Gln368Stop mutations are descended from a common founder. Although the specific mutations found in each of the five populations were different, the overall frequency of myocilin mutations was similar ( approximately 2-4%) in all populations, suggesting that the increased rate of glaucoma in African Americans is not due to a higher prevalence of myocilin mutations.

Asian People↗
PubMed1999

Glaucoma genetics: where are we? Where will we go?

The understanding of the genetic basis of the glaucomas has advanced rapidly. Mutations in the myocilin gene (previously known as TIGR) at the GLC1A locus on chromosome 1q21-q31 occur in a subset of patients with juvenile- and adult-onset primary open-angle glaucoma. Five other genetic localizations for primary open-angle glaucoma have now been reported. In patients with primary congenital glaucoma, mutations have been found in the CYP1B1 gene on chromosome 2p21. At least one other locus for primary congenital glaucoma is mapped. In the developmental glaucomas, mutations in the PITX2 gene on chromosome 4q25 have been associated with Rieger syndrome, iris hypoplasia, and iridogoniodysgenesis. A second locus for Rieger syndrome resides on chromosome 13q14. Mutations in the FKHL7 gene on chromosome 6p25 have been described in patients with Axenfeld-Rieger anomaly. A new ocular finding of glaucoma in pedigrees with the nailpatella syndrome has been described, and mutations in the LMX1B gene on chromosome 9q34 are now known to underlie nail-patella syndrome. Two loci for the pigment dispersion syndrome have been mapped. This paper provides an overview of recent literature, summarizes developments in glaucoma genetics, and addresses their potential relevance to the clinical management of glaucoma.

Eye Proteins↗
PubMed1998

Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A)

BACKGROUND: A substantial proportion of cases of glaucoma have a genetic basis. Mutations causing glaucoma have been identified in the chromosome 1 open-angle glaucoma gene (GLC1A), which encodes a 57-kd protein known as myocilin. The normal role of this protein and the mechanism by which mutations cause glaucoma are not known. METHODS: We screened 716 patients with primary open-angle glaucoma and 596 control subjects for sequence changes in the GLC1A gene. RESULTS: We identified 16 sequence variations that met the criteria for a probable disease-causing mutation because they altered the predicted amino acid sequence and they were found in one or more patients with glaucoma, in less than 1 percent of the control subjects. These 16 mutations were found in 33 patients (4.6 percent). Six of the mutations were found in more than 1 subject (total, 99). Clinical features associated with these six mutations included an age at diagnosis ranging from 8 to 77 years and maximal recorded intraocular pressures ranging from 12 to 77 mm Hg. CONCLUSIONS: A variety of mutations in the GLC1A gene are associated with glaucoma. The spectrum of disease can range from juvenile glaucoma to typical late-onset primary open-angle glaucoma.

Age of Onset↗