Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions.

PURPOSE: We seek to identify genetic loci that contribute to age-related maculopathy susceptibility. METHODS: Families consisting of at least two siblings affected by age-related maculopathy were ascertained using eye care records and fundus photographs. Additional family members were used to increase the power to detect linkage. Microsatellite genotyping was conducted by the National Heart, Lung and Blood Institute Mammalian Genotyping Service and the National Institutes of Health Center for Inherited Disease Research. Linkage analyses were conducted with parametric (autosomal dominant; heterogeneity lod score) and nonparametric methods (S(all) statistic) using three diagnostic models. False-positive rates were determined from simulations using actual pedigrees and genotyping data. RESULTS: Under our least stringent diagnostic model, model C, 860 affected individuals from 391 families (452 sib pairs) were genotyped. Sixty-five percent of the affected individuals had evidence of exudative disease. Four regions, 1q31, 9p13, 10q26, and 17q25, showed multipoint heterogeneity lod scores or S(all) scores of 2.0 or greater (under at least one model). Under our most stringent diagnostic model, model A, the 1q31 heterogeneity lod score was 2.46 between D1S1660 and D1S1647. Under model C, the 17q25 heterogeneity lod score at D17S928 was 3.16. Using a threshold of 1.5, additional loci on chromosomes 2 and 12 were identified. CONCLUSIONS: The locus on chromosome 1q31 independently confirms a report by Klein and associates mapping an age-related maculopathy susceptibility gene to this region. Simulations indicate that the 1q31 and 17q25 loci are unlikely to be false positives. There was no evidence that other known macular or retinal dystrophy candidate gene regions are major contributors to the genetics of age-related maculopathy.

Comparison of clinical characteristics of familial and sporadic acquired accommodative esotropia.

PURPOSE: To compare the clinical characteristics of patients with familial and nonfamilial acquired accommodative esotropia. METHODS: We recruited 48 patients from 33 families with acquired accommodative esotropia (an inward deviation of the eyes of 10 PD or more, a hypermetropia greater than or equal to +1.50 D, and an onset of esotropia at, or later than, 1 year of age). Our control group consisted of 20 patients with no known family history. Spherical error of refraction, stereoacuity, and need for strabismus surgery were determined and the 2 groups were compared. RESULTS: No statistically significant difference was found between the spherical equivalent error of refraction in familial cases (mean = +4.50 OD, +4.63 OS; range = +1.50 to +10.30 OD, +2.00 to +9.38 OS) versus those with nonfamilial disease (mean = +4.93 OD, +5.02 OS; range = +2.50 to +11.00 OD, +2.50 to +10.90 OS) (P =.47 OD; P =.47 OS). There also was no difference between the percentage of patients with familial disease who had some degree of stereoacuity (58%) and those without a family history (59%) (P > .99). Patients with familial acquired accommodative esotropia did not require more surgical interventions (26%) than those with nonfamilial acquired accommodative esotropia (30%) (P = .79). CONCLUSIONS: The general clinical characteristics of familial and nonfamilial acquired accommodative esotropia are very similar.

A full genome scan for age-related maculopathy.

Age-related macular degeneration or age-related maculopathy (ARM) is a major public health issue, as it is the leading cause of irreversible vision loss in the elderly in the Western world. Using three diagnostic models, we have genotyped markers in 16 plausible candidate regions and have carried out a genome-wide screen for ARM susceptibility loci. A panel of 225 ARM families comprising up to 212 affected sib pairs was genotyped for 386 markers. Under our most stringent diagnostic model, the regions with the strongest evidence of linkage were on chromosome 9 near D9S301 and on 10 near D10S1230, with peak multipoint heterogeneity LOD scores (HLOD) of 1.87 and 1. 42 and peak GeneHunter-Plus non-parametric LOD scores (GHP LOD) of 1. 69 and 1.83. After expanding our initial set of families to 364 ARM families with up to 329 affected sib pairs, the linkage signal on chromosome 9 vanished, while the chromosome 10 signal decreased to a GHP LOD of about 1.0, with a SimIBD P -value of 0.008 under the broadest diagnostic model with marker D10S1236. After error filtration, the GHP LOD increased to 1.27 under our most stringent model and 1.42 under our broadest model, peaking near D10S1236. This peak was seen consistently across all three diagnostic models. Our analyses also excluded up to nine different candidate regions and identified a few other regions of potential linkage, suitable for further studies. Of particular interest was the region on chromosome 5 near D5S1480, where a reasonable candidate gene, glutathione peroxidase 3, resides.

Congenital nasolacrimal duct obstruction: natural history and the timing of optimal intervention.

Nasolacrimal duct obstruction (NLDO) is a relatively common clinical problem. Debate continues about optimal management. Intervening early and intervening late each have advantages and disadvantages. We reviewed the world literature on NLDO. We assembled information on occurrence, natural history, and results of treatment. Spontaneous remission data were used to derive the probability of continued obstruction versus age. The prevalence a hypothesized treatment-resistant form of NLDO was estimated. Symptomatic NLDO probably occurs in 5 to 6% of infants. Given a symptomatic case under the age of 14 months, the probability of spontaneous remission within the following month appears to be approximately one of three. Probe failure risk increases with age, doubling every 6 months. Increasing probe failure risk may be due to self-selection. Preliminary analysis of management strategies suggests that lacrimal duct probing at age 4 months in the office is the most cost-effective strategy. Further descriptive studies of NLDO remission and treatment are indicated.

Angioid streaks associated with abetalipoproteinemia.

Angioid streaks were observed in two patients with abetalipoproteinemia. The progression of the angioid streaks was minimal over the years that these patients received vitamin A and E supplementation, though in one patient the development of subretinal neovascular membranes within the angioid streaks was the cause of rapid central visual loss. The simultaneous appearance of two rare entities in unrelated individuals strengthens the relationship between these two disorders that has been suggested by previous case studies. The authors propose a common metabolic pathway involving trace element deficiencies that may account for this relationship as well as the association of angioid streaks with other rare disorders such as Paget's disease, hypoparathyroidism, lead poisoning, hyperphosphatemia, and a number of hemoglobinopathies. Their study of these two patients underscores the need for further investigations as to the role of copper, zinc and omega-3 fatty acids in the pathogenesis of retinopathy in abetalipoproteinemia.

Congenital intrastromal epithelial cyst of the iris.

An 18-month-old boy presented with a six-month history of irritation OD. Examination under anesthesia found a 7 mm cyst involving the inferior aspect of the iris OD. There was elevated intraocular pressure, marked injection of the episclera and conjunctiva, and shallowing of the anterior chamber. The cyst was excised. Microscopic examination detected compression of the iris stroma that was caused by an intrastromal cyst lined with nonkeratinizing epithelium forming two layers. Most cystic lesions of the iris that arise during the neonatal period result from separation of the epithelial layers of the iris. In this case, in the absence of trauma, the cyst appeared to have resulted from a developmental inclusion of conjunctival epithelium into the iris stroma.

The heritability of strabismus.

The etiology of strabismus has long been observed to have a genetic component. Recent advances in genetic methodology may provide insight into the genetic basis for several types of inherited strabismus, including those associated with genetic multisystem disorders such as Moebius syndrome, Prader-Willi syndrome, craniofacial dysostoses, and mitochondrial myopathies. Inheritance of primary forms of strabismus, such as congenital ocular fibrosis, Brown syndrome and Duane syndrome, has been reported, but less is known of the defective genetic sites. The genetic basis for isolated strabismus that clusters in families, such as infantile esotropia syndrome, is also not yet known, but new techniques of molecular biology may now permit linkage detection in these families. By identifying affected families, clinicians will take part in unraveling the genetic basis of hereditary strabismus syndromes.

Orbital cellulitis following strabismus surgery.

Orbital cellulitis is a rare complication of extraocular muscle surgery. Two cases have been reported since 1935. No report of this sight-threatening and life-threatening complication of strabismus surgery has appeared since computerized tomography became readily available. The following is a report of a case of orbital cellulitis occurring unilaterally following bilateral strabismus surgery in which computerized tomography was helpful in verification and management. Early antibiotics resulted in a favorable outcome. The case is compared to those reported by von Noorden.

Medical management of congenital nasolacrimal duct obstruction.

Fifty-five infants were diagnosed to have nasolacrimal duct obstruction by an ophthalmologist prior to three months of age. All were followed prospectively, primarily with medical management. Seven were treated surgically. In the 55 infants, there were 62 obstructed nasolacrimal ducts. Eighty-nine percent (55/62) of the nasolacrimal ducts were opened with medical management only in the first sixteen months of life. Of the nasolacrimal ducts that opened spontaneously, 15% (8/55) were open at three months, 45% (25/55) were open at six months, 71% (39/55) were open at nine months, and 93% (51/55) were open at one year. Based on this data one can advise the parents of infants with nasolacrimal duction what the odds of remission are without surgery by the twelfth month of age. Of the infants obstructed at three months of age, 80% were clear by the twelfth month. Of the infants obstructed at six months, 70% were clear by the twelfth month and of those still obstructed at nine months, 52% were clear by the twelfth month.

Metastatic coccidioidal endophthalmitis.

A severe granulomatous iridocyclitis developed in association with a cavitary pulmonary lesion in a 29-year-old man. The initial diagnosis and treatment was for pulmonary tuberculosis with tuberculous uveitis. Although the pulmonary lesion improved with antituberculous therapy, the condition of the eye deteriorated. An anterior-chamber tap was positive for Coccidioides immitis, and the patient was treated with intravenous and two intracameral injections of amphotericin B. The eye was ultimately enucleated three weeks after the initial intracameral injection, and yet was culture-positive for the organism. Histopathologic examination disclosed diffuse involvement of the anterior segment, with multiple spherules present within the iris and limbus.

Mangement of infantile esotropia.

We evaluated the management of infantile esotropia-constant, alternating esotropia before 6 months of age-in 34 children. Planned one-state surgery for satisfactory mechanical alignment was highly predicatable (79 to 84%), and was obtained at any age. Stable bifoveal motor fusion was also obtained but was more frequent with alignment before 2 years of age. The use of postsurgical spectacle orthoptics (minus lenses or prisms, or both) increased the incidence of bifoveal fusion. Surgery alone resulted in bifoveal fusion in 6% of the cases, whereas an overall incidence of 33% bifoveal fusion resulted after the use of postsurgical spectacle orthoptics by some patients. Of those receiving postsurgical spectacle orthoptics, 53% obtained bifoveal fusion. This study demonstrated a correlation between the incidence of secondary A patterns (after surgery for V esotropia) and the amount of horizontal muscle surgery done in combination with bilateral inferior oblique muscle myectomies.

Funduscopic appearance of papilledema with optic tract atrophy.

In a child with a hypothalamic glioma, elevated intracranial pressure and retrograde optic tract atrophy produced distinctive patterns of papilledema and disc pallor in each eye. On the side of the tract lesion, the disc was swollen nasally and was pale temporally. In the contralateral fundus, the swollen optic disc was bisected horizontally by a pale atrophic band. These funduscopic signs exemplify a rare instance in neuro-ophthalmologic diagnosis wherein specific lateralizing and localizing information can be deduced solely from the appearance of papilledema.