Cataract in gyrate atrophy: clinical and morphologic studies.

The clinical appearance of the cataract in nine phakic patients with gyrate atrophy of the choroid and retina is described. The gross and microscopic examination of three cataractous lenses removed from patients 31 years to 47 years of age is reported. Clinically, the lens opacities appeared primarily along the confluence of the sutures posteriorly, interfering with vision because of their location in the visual axis. Histologically the region of the posterior sutures was filled with liquified and degenerated lens material typical of senile cataractous changes. By the second decade, cataract is a uniform finding in patients with gyrate atrophy and appears to be unique as compared with cataracts associated with other forms of retinal degeneration.

Expression defect of ornithine aminotransferase gene in gyrate atrophy.

A generalized deficiency in the mitochondrial enzyme, ornithine aminotransferase (OAT: EC 2.6.1.13), is the hallmark of gyrate atrophy (GA), a hereditary degenerative disease of the choroid and retina of the eye that leads to blindness. A human OAT cDNA, previously constructed and characterized in our laboratory, and anti-human OAT antibody were used as probes to examine the OAT gene, mRNA and protein of GA patients. A blot analysis of the genomic DNAs, RNAs and proteins of 14 GA patients identified a case with a partial heterozygous deletion of the functional OAT gene located on chromosome 10, no detectable OAT mRNA, and a barely detectable level of OAT antibody-reactive protein. The rest of the cases showed grossly normal OAT gene, mRNA, and variably reduced levels of OAT protein. A restriction fragment length polymorphism (RFLP) was identified in the functional OAT gene sequence with EcoRI which may be useful for prenatal diagnosis of GA. RFLPs were also identified in the OAT-related gene sequences located on the X chromosome with Hind III and Pst I which may potentially show linkage to X-linked retinitis pigmentosa locus. The finding of an OAT gene, mRNA, and protein defect in a GA case constitutes the first real demonstration of the molecular genetic defect of OAT in GA.

A double-masked study of timolol and pilocarpine combined.

In a double-masked, randomized, multicenter study, 25 patients received timolol 0.5%-pilocarpine 2% twice a day, 25 received timolol 0.5%-pilocarpine 4% twice a day, and 25 received pilocarpine 4% four times a day. The combination drugs showed an immediate, significant reduction in intraocular pressure of 7.2 mm Hg (25%) and 10.7 mm Hg (37%), respectively. The lowered intraocular pressure level was maintained throughout the three-week test period. With pilocarpine alone, intraocular pressure was reduced 5.3 mm Hg (19%). The mean intraocular pressure 12 hours after the last dose compared to two hours after the last dose was significantly higher both in patients receiving pilocarpine four times a day and in patients receiving timolol 0.5%-pilocarpine 4% twice a day (5.1 and 3.6 mm Hg, respectively), but not in patients receiving timolol 0.5%-pilocarpine 2% twice a day (2.6 mm Hg).

The natural history of gyrate atrophy of the choroid and retina.

Twenty-nine Finnish patients (8-80 years old during follow-up) with hyperornithinemia and gyrate atrophy (HOGA) were followed 2 to 31 years to determine when and how rapidly visual acuities and visual functions were affected by the disease. Considerable variability was observed both in the age at which visual acuities began to decrease and the age at which visual acuities reached 20/200. Acuities in phakic eyes tended to decrease from 20/30 to 20/200 in ten years or less, while aphakic eyes exhibited generally slower loss of vision. Without benefit of cataract surgery, the percentage of eyes with acuity 20/200 or worse would have been 37% at age 30 and 64% at age 40, but through surgery actually performed was 20% at age 40. Constriction of visual fields with age was marked and correlated well with diminution in dark adaptation.

The IOP-lowering effect of timolol in simple and capsular glaucoma. A multicenter study in Finland.

Timolol maleate eye drops (0.25% and 0.5%) were used alone or in combined treatment in 220 patients with simple or capsular glaucoma. A highly significant (P less than 0.001, mean -9.4 mm Hg,-29%) decrease in the intraocular pressure (IOP) was seen in 196 (164 simple, 32 capsular) patients in the beginning of the study using timolol alone. (Inadequate control timing, deviation from the treatment definition, or adverse reactions caused the exclusion of the data of 24 patients). A total of 180 patients (151 simple, 29 capsular) completed the 6-month study. At the end of the study an IOP less than 22 mm Hg was seen in 103 (57.2%, 91 simple, 12 capsular) patients treated with timolol alone. During the follow-up period there was no significant difference in the IOP-lowering effect of timolol in the simple and the capsular group using timolol alone. Combined treatment was needed by 39 of 180 patients who completed the study. It was needed more than twice as often in the capsular group (12 patients, 41.4%) as in the simple group (27 patients, 17.9%). The IOP increased above 25 mm Hg in one-fourth of these 39 patients during the follow-up period, but there was no significant difference between the simple and the capsular group. Six patients dropped out of the study because of side-effects possibly related to timolol therapy.

Gyrate atrophy of the choroid and retina. Biochemical considerations and experience with an arginine-restricted diet.

Ornithine-delta-aminotransferase deficiency is the primary biochemical defect in gyrate atrophy of the choroid and retina and results in the characteristic accumulation of ornithine. An additional consequence of this inborn error is that arginine, the precursor of ornithine, becomes an essential amino acid. Therefore, to reduce the accumulated ornithine, we placed nine gyrate atrophy patients on an arginine-restricted diet. Plasma ornithine decreased by 50 to 85% within one month. Orally administered, alpha-aminoisobutyric acid facilitated the reduction in ornithine by augmenting renal losses. Over the long term, three patients have maintained near normal plasma ornithine concentrations from 4 to 32 months. Two patients have maintained less striking reductions in ornithine, and four have either been poorly controlled or have terminated the diet. Urinary losses of arginine and ornithine in gyrate atrophy patients with high or low plasma ornithine concentrations are less than 50% of the estimated arginine intake. This observation suggests that the bulk of ingested arginine is somehow metabolized despite the severe reduction in ornithine-delta-aminotransferase activity.

Timolol treatment of chronic open-angle glaucoma and ocular hypertension. A 2.5-year multicenter study.

Maintenance effect of topical timolol was investigated for 2 years in a group of 125 glaucomatous and ocular hypertensive patients (231 eyes) who had been successfully treated with timolol alone during a 6-month period preceding this trial. Intraocular pressure (IOP) was controlled with timolol alone in 135 of 183 eyes (74%) that completed the study. At the end of the trial 142 eyes (78%) showed an IOP of less than 22 mmHg. Other glaucoma medication had to be added to timolol treatment in 18% of ocular hypertensive and 35% of glaucomatous eyes because of IOP elevation. Elevation of IOP seemed to be due to worsening of glaucoma rather than to decreased efficacy of timolol. None of the ocular hypertensive patients developed visual field defects but in ten glaucomatous patients progression of existing visual field defects was observed in association with elevated IOP. Transient adverse effects were observed in 13% of cases, but timolol treatment had to be stopped in only five cases (4%) because of side effects.

Systemic manifestations of gyrate atrophy of the choroid and retina.

In ten patients with gyrate atrophy (GA) and hyperornithinemia, the head hair was fine, straight, and sparse. On microscopic examination, both scalp and pubic hair contained intermittent dark cores within the medullary zone, which was not a deposit, but appeared to be due to the unusual refractive properties of loosely formed macrofilaments amidst wide spaces containing a structureless electron lucent but compact substance, which was insoluble in both water and solvents. Seven of the ten patients had abnormal wave forms on electroencephalography. Three of the five patients who underwent muscle biopsy had tubular aggregates. Of particular interest was the toxicity of exogenous ornithine added to muscle cell culture from GA patients as compared with the lack of toxicity in muscle from control patients. What specific role the hyperornithinemia and absence of OAT is playing in the histopathology of hair and muscle and the EEG changes awaits further biochemical investigation.