Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eyedrops.

Although renal disease is the most prominent feature of the lysosomal storage disease cystinosis, corneal cystine crystal formation remains a major complication, leading to photophobia, corneal erosions, and keratopathies. Moreover, the extent of corneal crystal accumulation reflects the course and severity of the disease itself, and the cornea is accessible to direct examination. Therefore, we employed a scoring system, based on a library of slit-lamp photographs of corneas with increasing crystal densities (0.00-3.00), to assess the degree of crystal accumulation in 170 patients with nephropathic cystinosis examined at the National Institutes of Health between 1976 and 2000. None of the patients had received topical cystine-depleting therapy at the time of the evaluation. In this natural history study, infants in the first year of life had absent or minimal corneal crystals, i.e., a corneal cystine crystal score (CCCS) of 0 or 0.25. However, the CCCS increased linearly with age, such that every patient had visible crystals by 16 months of age, and plateaued at approximately 3.00 by early adolescence. Longitudinal studies in representative patients support the cross-sectional results. Individuals homozygous for the common 57-kb deletion involving the cystinosis gene (CTNS) displayed the same course of corneal crystal accumulation as did individuals not bearing the large deletion. Patients with ocular or nonnephropathic cystinosis had CCCSs that were, in general, half those expected for patients with nephropathic cystinosis of the same age. Administration of 0.55% cysteamine eyedrops, given 6 to 12 times per day, dissolved corneal cystine crystals in 10 representative patients with nephropathic cystinosis aged 1 to 32 years within 8 to 41 months.

Correlation of visual acuity and ocular pigmentation with the 16-bp duplication in the HPS-1 gene of Hermansky-Pudlak syndrome, a form of albinism.

OBJECTIVE: Patients with the Hermansky-Pudlak syndrome (HPS), a form of albinism, were studied. The first purpose of this investigation was to determine if visual acuity was related to the presence or absence of the 16-bp duplication in the HPS-1 gene. The second was to study the correlation between the degree of ocular pigmentation and visual acuity within the two genetic groups described above. DESIGN: Cross-sectional study of a series of consecutive patients. PARTICIPANTS: Forty-nine patients with HPS with or without the 16-bp duplication in HPS-1. METHODS: Best corrected visual acuity (VA) using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, photographic gradings of iris transillumination and of visibility of choroidal vessels in the macula (macular transparency). MAIN OUTCOME MEASURES: Association between VA and the presence or absence of the 16-bp duplication in HPS-1 and correlation between VA and the degree of iris transillumination (iris score) and macular transparency (fundus score), as determined by masked reading of photographs, with respect to the presence or absence of the 16-bp duplication in HPS-1 were the main outcome measures. RESULTS: The VA of the better eye did not differ between the two genetic groups (P = 0.322, two-sided t test). Spearman's rank correlation between VA and iris scores in 39 eyes of 20 patients with the duplication was not statistically significant (P = 0.698) but was statistically significant in 36 eyes of 19 patients without the duplication (P < 0.001). Among all patients, the correlation was statistically significant (r = -0.36 in RE and r = -0.51 in LE). Spearman's rank correlation between VA and fundus scores in 36 eyes of 19 patients with and 34 eyes in 18 patients with and without the duplication was statistically significant (P = 0.035 and P = 0.008, respectively). Among all patients, it was also statistically significant (r = -0.39 in RE and r = -0.45 in LE). CONCLUSIONS: The mean VA of the better eye did not differ in patients with the 16-bp duplication compared with those without the duplication. There were statistically significant associations between VA and the iris score and the fundus score except for the VA and iris scores in patients with the 16-bp duplication. However, because of the variability of VA, these associations were not large enough for useful prediction of VA based on the degree of ocular pigmentation.

A randomized clinical trial of topical cysteamine disulfide (cystamine) versus free thiol (cysteamine) in the treatment of corneal cystine crystals in cystinosis.

In nephropathic cystinosis, corneal cystine crystals cause severe photophobia and corneal erosions. Topical cysteamine dissolves these crystals, but cannot be marketed because it rapidly oxidizes to the disulfide form, cystamine, at room temperature. Since cystamine itself could be used commercially, we compared the efficacy of cystamine and cysteamine with respect to cystine crystal dissolution in a randomized, double-masked clinical trial. One eye each of 14 patients with cystinosis was randomized to either cystamine or cysteamine, 0.5%, with 0.01% benzalkonium chloride; the companion eye was treated with the alternate preparation. Corneal crystals were photographed and a density score was assigned to each slide based on 13 standard slides. After 8-20 months, 6 patients showed significant reduction of the corneal crystal score in only one eye. In each case, the improved eye was the cysteamine-treated eye. Theoretically, cysteamine should dissolve both intracellular and extracellular crystals, whereas cystamine should dissolve only intracellular crystals because it must first be reduced to the free thiol by the cytoplasmic-reducing environment. Hence, the lack of efficacy of the disulfide cystamine suggests that some corneal cystine crystals in cystinosis patients are extracellular, and that another form of stable, topical cysteamine must be developed for cystinosis patients.

Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome).

BACKGROUND: Hermansky-Pudlak syndrome is characterized by oculocutaneous albinism, a storage-pool deficiency, and lysosomal accumulation of ceroid lipofuscin, which causes pulmonary fibrosis and granulomatous colitis in some cases. All identified affected patients in northwest Puerto Rico are homozygous for a 16-bp duplication in exon 15 of a recently cloned gene, HPS. We compared the clinical and laboratory characteristics of these patients with those of patients without the 16-bp duplication. METHODS: Forty-nine patients -- 27 Puerto Ricans and 22 patients from the mainland United States who were not of Puerto Rican descent -- were given a diagnosis on the basis of albinism and the absence of platelet dense bodies. We used the polymerase chain reaction to determine which patients carried the 16-bp duplication. RESULTS: Twenty-five of the Puerto Rican patients were homozygous for the 16-bp duplication, whereas none of the non-Puerto Rican patients carried this mutation. Like the patients without the duplication, the patients with the 16-bp duplication had a broad variation in pigmentation. Nine of 16 adults with the duplication, but none of the 10 without it, had a diffusing capacity for carbon monoxide that was less than 80 percent of the predicted value. High-resolution computed tomography in 12 patients with the 16-bp duplication revealed minimal fibrosis in 8, moderate fibrosis in 1, severe fibrosis in 1, and no fibrosis in 2. Computed tomography in eight patients without the duplication revealed minimal fibrosis in three and no fibrosis in the rest. Inflammatory bowel disease developed in eight patients (four in each group) between 3 and 25 years of age. CONCLUSIONS: The 16-bp duplication in exon 15 of HPS, which we found only in Puerto Rican patients, is associated with a broad range of pigmentation and an increased risk of restrictive lung disease in adults.

Constructing retinal fundus photomontages. A new computer-based method.

PURPOSE: To develop computer algorithms for reconstructing 24-bit color, wide-angle composite retinal fundus images from a set of adjacent 45 degrees fundus slides. The authors present the description, technical details, and results of the image reconstruction technique. METHODS: Patients with retinal degeneration underwent fundus photography with a 45 degrees field-of-view fundus camera. Individual photographic slides were digitized for creating fundus montages. Background variations in individual 45 degrees images were modeled to first- or second-order two-dimensional polynomial functions to generate a background image. The background image was subtracted from the original image to obtain background corrected image. Background corrected images were registered and spatially transformed using a first- or second-order two-dimensional polynomial warp model to reconstruct a composite retinal fundus montage. RESULTS: The authors successfully reconstructed 24-bit color, 100 degrees field-of-view, composite retinal fundus images. The computer-reconstructed montages are an improvement over manually generated montages because computer analysis can be performed on the computer-based montages. In addition, background variations and discontinuities between individual photographs observed in manually generated montages are reduced greatly in computer-generated montages. Most important, the computer-generated montages are better aligned than the manually generated photomontages. CONCLUSIONS: This method of reconstructing a wide-angle composite retinal fundus image from a set of adjacent small- and wide-angle fundus slides is a new tool for creating montages as large as 100 degrees field of view. The computer-generated montages may be used for documenting and quantifying retinal findings. This can greatly assist studies of retinal manifestations of diseases, such as gyrate atrophy, retinitis pigmentosa, sickle cell disease, and acquired immune deficiency syndrome.

A randomized placebo-controlled trial of cysteamine eye drops in nephropathic cystinosis.

Eighteen patients with nephropathic cystinosis who were younger than 42 months and 11 patients 4 to 31 years of age were entered into a double-masked, randomized, placebo-controlled trial of topical cysteamine eye drops between November 1985 and September 1989. Eight of the younger patients and 2 of the older patients showed marked clearing of corneal crystals in one eye compared with the fellow eye. When the code was broken, all 10 patients were found to have received cysteamine eye drops in the improved eye. Of the remaining 19 patients 4 were unavailable for follow-up. In 15 patients no marked difference was noted between the two eyes. Eight have presumably been in the protocol for too short a time and several have been poor compliers with the therapy. These results not only demonstrate the potential for primary prevention of corneal crystal deposition but also, for the first time, offer the possibility of reversing the corneal complications of cystinosis in older patients.