Nail-patella syndrome and its association with glaucoma: a review of eight families.

BACKGROUND: Nail-patella syndrome (NPS) is a rare autosomal dominant syndrome, characterised by dysplasia of the nails, patellae, elbows and iliac horns. Mutations in the LMX1B gene were found in four North American families in whom glaucoma cosegregated with NPS. AIMS: To investigate the association of glaucoma with NPS in Australian families and to determine how common NPS is in Australia. METHODS: One family with NPS and glaucoma was identified from the Glaucoma Inheritance Study in Tasmania. A further 18 index cases of NPS were identified from the genetics database for southeastern Australia. Eight of these pedigrees were available for comprehensive glaucoma examination on available family members. DNA was sequenced for mutations in LMX1B. RESULTS: In total, 52 living cases of NPS were identified suggesting a minimum prevalence of at least 1 in 100 000. 32 subjects from eight NPS pedigrees (four familial and four sporadic cases) were examined. 14 subjects had NPS alone. 4 subjects had NPS and glaucoma or ocular hypertension. Five pedigrees with NPS had a reported family history of glaucoma, although some of these people with glaucoma did not have NPS. LMX1B mutations were identified in 5 of the 8 index cases-three sporadic and two familial. Two of the six (33%) participants over 40 years of age had developed glaucoma, showing increased risk of glaucoma in NPS. CONCLUSION: Patients with NPS should be examined regularly for glaucoma. However, because the families with NPS are ascertained primarily from young probands or probands who are isolated cases, the exact level of risk is unclear.

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.

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

Systemic effects of topical ophthalmic beta-adrenoceptor antagonists.

Topical ophthalmic beta-adrenoceptor antagonists (beta-blockers) are generally recognized as the treatment of choice in glaucoma management due to favourable efficacy, safety and tolerability. Despite topical ocular administration, beta-blockers are systemically absorbed, in relatively small amounts, through the nasolacrimal drainage system and can adversely affect cardiovascular and pulmonary function. While cardioselective beta-blockers, such as betaxolol, possibly confer an advantage with respect to clinical safety through their receptor affinity, systemic effects are also influenced by other pharmacological factors, including the rate and extent of systemic absorption and the extent of plasma protein binding. These factors are reviewed to distinguish the various ophthalmic beta-blockers and to explain the observed clinical differences in the safety profiles of these medications.

The problem of overlapping glaucoma families in the Glaucoma Inheritance Study in Tasmania (GIST).

The Glaucoma Inheritance Study in Tasmania (GIST) is a population survey of Australia's island state, Tasmania (population 450,000). Its aim is to find families with autosomal dominant, adult-onset, primary open angle glaucoma (POAG) suitable for genetic linkage analysis. POAG is relatively common, affecting around 3% of the Australian population. By finding the large families with POAG and identifying all the descendants in a captive population, it is possible that there may be overlap of different glaucoma pedigrees. Three of the first thirteen families in the study were composed of overlapping pedigrees. In one GIST family, GTas3, there has been intermarriage with other pedigrees with glaucoma on five occasions. The possibility of multiple genotypes was also reinforced by the inability to determine a single glaucoma phenotype in this family. When finding large families of POAG for linkage analysis, researchers must be aware of the risk of affected individuals inheriting their gene from the alternate parent. Thus, the alternate parents or their families must be examined, especially if the phenotype is atypical for the rest of the family.

Fastpac visual field screening.

In epidemiology, screening for visual field defects has traditionally been expensive, time consuming and laborious. To achieve cost- and time-effective visual field screening, a faster algorithm has been developed for the Humphrey perimeter called Fastpac, which is designed to achieve threshold perimetry in two-thirds the time of the standard algorithm. We compared the Fastpac and conventional full-threshold 24-2 fields obtained in 39 eyes of 36 participants. We divided the participants' fields into normal (14) and glaucomatous (25) visual field groups, and compared the test times, number of questions asked and statistical parameters generated for each field for Fastpac as compared to the standard algorithm. Then we divided the participants' fields into Fastpac and standard fields and again compared the test times, number of questions and statistical parameters. Finally we asked trained observers to judge the fields as being normal or abnormal, in a masked fashion, and found a high degree of agreement between the fields generated by Fastpac and standard. Fastpac offers accurate full-threshold screening in two-thirds the time of the conventional algorithm and would be very useful for large scale prevalence studies in ophthalmic epidemiology.

Comparison between Fastpac and conventional Humphrey perimetry.

As part of the Melbourne Visual Impairment Project, a substudy was performed to determine the efficacy of the newly released Fastpac program for the Humphrey Field Analyser. A comparison was performed of the Fastpac and conventional full threshold 24-2 fields obtained in 39 eyes of 36 participants. Also a comparison study was performed of the standard and non-standard 80-point screening tests to the standard 24-2 full threshold test in 23 eyes of 23 participants. In the full threshold comparison there was 100% agreement between the two with Fastpac being 32% to 39% faster than standard. In the 80-point screening test comparison, non-standard was no faster than standard. Sensitivities were 17/17 (1.0) for non-standard and 15/18 (0.83) for standard, as compared with the standard 24-2 full threshold test. Fastpac software offers accurate screening and threshold testing in less time than the standard algorithm.

Trabeculectomy with releasable sutures.

OBJECTIVE: To determine whether the use of releasable scleral-flap sutures affects the success rate and the incidence of complications following trabeculectomy. DESIGN: A retrospective chart review of a consecutive series of trabeculectomies. SETTING: A university-based referral practice. PATIENTS: Two hundred fifty-eight consecutive patients (274 eyes) undergoing trabeculectomy because of uncontrolled glaucoma. INTERVENTION: During the first year, 124 patients (128 eyes) underwent trabeculectomies with permanent scleral-flap sutures. During the second year, 134 patients (146 eyes) underwent trabeculectomies with releasable scleral-flap sutures. MAIN OUTCOME MEASURES: Incidence of flat and shallow anterior chamber, incidence of operations to drain choroidal detachment and to re-form anterior chamber, and long-term control of intraocular pressure. RESULTS: In the group with permanent sutures, 42 eyes (32.8%) had clinically detectable shallowing of the anterior chamber in the early postoperative period. In contrast, a shallow anterior chamber was noted in 21 eyes (14.4%) in the group with releasable sutures (P = .0003). Flat anterior chamber, defined as iridocorneal apposition to the pupil margin, occurred in 11 eyes with permanent sutures (8.6%) but in only two eyes (1.4%) with releasable sutures (P = .0078). Surgical intervention to drain suprachoroidal fluid and re-form the anterior chamber was required in eight eyes with permanent sutures (6.2%) but in only one eye with releasable sutures (0.7%) (P = .014). At 1-year follow-up, the two groups were similar in terms of intraocular pressure and the need for ocular hypotensive medications. CONCLUSIONS: Releasable scleral-flap sutures reduce the incidence of shallow and flat anterior chamber after trabeculectomy without compromising long-term control of intraocular pressure.

Trabeculectomy with releasable sutures.

We attempted to reduce some of the postoperative complications of trabeculectomy by using releasable scleral flap sutures. This technique allows an initial tight closure of the scleral flap with the option to increase aqueous humor outflow in the early postoperative period. We reviewed our experience with trabeculectomy and releasable sutures in 146 eyes (134 patients) and compared these cases with a prior series of 128 eyes (124 patients) that underwent trabeculectomy with permanent scleral flap sutures. In the control group, 42 eyes (32.8%) had clinically detectable shallowing of the anterior chamber in the postoperative period. In contrast, shallow anterior chamber was noted in 21 eyes (14.4%) in the group with releasable sutures (P = .0003). Flat anterior chamber, defined as iridocorneal touch to the pupil margin, occurred in 11 control eyes (8.6%) but in only 2 eyes (1.4%) with releasable sutures (P = .0078). Surgical intervention to drain suprachoroidal fluid and re-form the anterior chamber was required in eight control eyes (6.2%) but in only one study eye (0.7%) (P = .014). At 1 year of follow-up, the two groups were similar in terms of mean intraocular pressure, the need for ocular hypotensive medications, and failure rate.

Public hospital day-case surgery in a dedicated facility.

The first dedicated, public hospital day-case eye surgery unit opened in Melbourne in June 1987. This report details the mode of operation of this unit, and analyses the 218 procedures performed in the first 15 months of operation, and includes an assessment of the level of patient acceptance.

Acute macular neuroretinopathy.

The presentation of bilateral incongruous paracentral scotomata in an otherwise well 21 year old woman was found to correspond to dark, red-brown, wedge-shaped lesions surrounding the macula. Like previously described cases of acute macular neuroretinopathy, these lesions seemed to be located in the superficial retina and appeared to be associated with oral contraceptive use and a recent history of viral illness. At follow-up 8 months after presentation, the scotomata were persistent and unchanged. No treatment is known.