Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy.

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892 , USA.
Ophthalmology (Impact Factor: 6.14). 07/2006; 113(6):1002-9.
Source: PubMed


Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by the intracellular accumulation of cystine. Treatment involves intracellular cystine depletion with oral cysteamine. A wide spectrum of ocular pathologic features has been associated with nephropathic cystinosis. We used the largest documented cohort of patients in the world to study the posterior segment manifestations associated with infantile nephropathic cystinosis and to determine retrospectively the effect of chronic oral cysteamine therapy on the frequency of these abnormalities.
Cross-sectional study of a series of patients.
Two hundred eight patients with infantile nephropathic cystinosis were studied at the National Institutes of Health between 1976 and 2004.
All patients underwent an ophthalmic evaluation. Patients older than 11 years also underwent Humphrey static perimetry, and electrophysiological testing was performed when possible.
Visual acuity, retina findings, visual fields, and electroretinographic (ERG) findings.
Pigmentary changes with retinal pigment epithelial mottling, seen as early as infancy, were the most common posterior segment manifestations. Moderate to severe constriction of the visual fields, as well as moderate to severe reduction of rod- and cone-mediated ERG responses, was seen in older patients. The frequency of retinopathy correlated directly with time not receiving oral cysteamine therapy and inversely with time receiving oral cysteamine therapy.
Infantile nephropathic cystinosis has posterior segment complications that can contribute to significant visual handicap. Early initiation of oral cysteamine therapy can reduce the frequency of posterior segment complications in cystinosis patients.

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    • "Crystal accumulation in the conjunctiva and cornea, and pigmentary retinopathy are originally the most commonly described ophthalmic manifestations of cystinosis. Although patients with ocular cystinosis do not exhibit a retinal pigment abnormality, posterior segment involvement associated with retinal degeneration have been described in infantile nephropathic cystinosis [10]. The most common retinal finding in these eyes was patches of depigmentation in the periphery with pigmentary mottling [10]. "
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    ABSTRACT: To report clinical features of bilateral angle-closure glaucoma in a patient with nanophthalmic eyes associated with ocular cystinosis, foveoschisis and pigmentary retinal dystrophy. This is probably the first published report of the possible association of all these five entities in the same patient. A 50-year-old white male was referred for uncontrolled glaucoma in both eyes. He was previously diagnosed with angle-closure glaucoma in association with ocular cystinosis. Ocular examination revealed high hyperopia (+13.5 OD and +14 OS diopters) with reduced axial length (16.27 mm OD and 15.93 mm OS). Despite being on 3 topical medications, his IOP measured 37 mmHg OD and 35 mm Hg OS. Slit-lamp biomicroscopy showed refractile, polychromatic crystalline deposits throughout the cornea and conjunctiva in both eyes. Gonioscopy revealed an extremely narrow angle with peripheral anterior synechiae (PAS). Anterior chamber depths were shallow. Fundus examination disclosed punctate hypopigmentation of the retinal pigment epithelium mainly at the posterior pole. Optical coherence tomography showed foveal schisis appearing as small retinal cysts. The patient did not display any systemic abnormalities. This case brings into discussion a new clinical entity of angle closure glaucoma in nanophthalmos accompanied by ocular cystinosis-foveoschisis-pigmentary retinal dystrophy complex.
    BMC Ophthalmology 07/2012; 12(1):23. DOI:10.1186/1471-2415-12-23 · 1.02 Impact Factor
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    • "The low levels of intracorneal cysteamine achieved via topical application are thought to result from poor compliance, limited corneal penetration and drug instability [15,21,22,27-31]. Development of alternative treatments for corneal disease has been hampered by the need for costly and time consuming human clinical trials in this low prevalence disease [20,32,33]. "
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    ABSTRACT: The purpose of this study was to assess the ability of quantitative in vivo confocal microscopy to characterize the natural history and detect changes in crystal volume in corneas from a novel animal model of cystinosis, the cystinosin (Ctns(-/-)) mouse. Two Ctns(-/-) mice and one C57Bl/6 mouse were examined at each of the following time points: 2, 3, 5, 7, 10, 12, and 14 months of age. In vivo confocal microscopy scans were performed in 4 different regions of the cornea per eye. After, animals were sacrificed and cornea blocks evaluated for cell morphology using phalloidin and lymphocytic infiltration using CD45 antibodies by ex vivo confocal microscopy. Cystine crystal content in the cornea was measured by calculating the pixel intensity of the crystals divided by the stromal volume using Metamorph Image Processing Software. Corneal crystals were identified in Ctns(-/-) eyes beginning at 3 months of age and increased in density until 7-12 months, at which time animals begin to succumb to the disease and corneas become scarred and neovascularized. Older Ctns(-/-) mice (7 months and older) showed the presence of cell infiltrates that stained positively for CD45 associated with progressive keratocyte disruption. Finally, at 12 months of age, decreased cell density and endothelial distortion were detected. Confocal microscopy identified corneal crystals starting at 3 month old Ctns(-/-) eyes. Cystine crystals induce inflammatory and immune response with aging associated with loss of keratocyte and endothelial cells. These findings suggest that the Ctns(-/-) mouse can be used as a model for developing and evaluating potential alternative therapies for corneal cystinosis.
    Molecular vision 08/2011; 17:2212-20. · 1.99 Impact Factor
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    • "Because of their relatively low prevalence , cystinosis and cysteamine can be considered as an orphan disease and orphan drug, respectively [8]. Despite the lack of pharmaceutical industry interest in developing new medications to treat rare diseases such as cystinosis, many researches have been carried out in an effort to contribute to the treatment of both nephropathic and ocular cystinosis [9] [10] [11] [12] [13]. "
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    ABSTRACT: In the present study, viscous solutions of cysteamine hydrochloride (CH) were prepared by using 0.5%, 1.0%, 1.5% or 3.0% of hydroxypropylmethylcellulose (HPMC) and were evaluated for their in-vitro characteristics and stability. Osmolalities, pH and viscosity of the formulations were determined. The influence of benzalkonium chloride and autoclave sterilization on solution characteristics was also investigated. For stability assessment, the viscous solutions were stored at +4 and +25 °C over 12 months. In-vitro characteristics and CH contents of the stored solutions were monitored. Irritation tests for the formulations were evaluated on rabbit eyes. Dialysis sac technique was used to perform in vitro release study of the solutions containing 1.0% and 1.5% HPMC. All of the viscous solutions tested showed non-newtonian (dilatant) flow behavior. Osmolality values were ranked between 351.2 ± 6.2 and 355.1 ± 7.9 mOsm kg−1, and pH values were between 3.97 ± 0.1 and 3.98 ± 0.2 for all the solutions. Furthermore, no significant changes in dilatant behavior, osmolality or pH values of the pure HPMC solutions were observed. After addition of the excipients or CH-excipients, increased viscosity values were noted in these formulations. Neither benzalkonium chloride nor autoclave sterilization had any influence on viscosity, pH or osmolality values of the solution containing 1.5% HPMC. Stability studies showed that a faster decrease in the concentration of CH was observed in the formulations stored at 25 °C compared to those kept at 4 °C; no changes were determined in osmolality values of the solutions at all storage conditions. Increased pH and decreased viscosity values were noted in HPMC solutions containing CH and excipients, while no changes in these values were observed for pure HPMC solutions kept at 4 and 25 °C. In vitro release tests revealed that 81.2% and 85.3% of CH were released from the viscous solutions containing 1.5% and 1% HPMC, respectively, in 8 h. No irritation was observed when the viscous solutions were tested on rabbit and human eyes.
    European Journal of Pharmaceutics and Biopharmaceutics 09/2008; 70(1-70):260-269. DOI:10.1016/j.ejpb.2008.04.010 · 3.38 Impact Factor
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