Cystine Crystal Deposition Research Articles

A rabbit model of cystinosis has deposition of cystine crystals in the cornea

A rabbit model of cystinosis has deposition of cystine crystals in the cornea

Recent Research in Ocular Cystinosis: Drug Delivery Systems, Cysteamine Detection Methods and Future Perspectives.

Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in different tissues and organs. Although renal damage prevails during initial stages, the deposition of cystine crystals in the cornea causes severe ocular manifestations. At present, cysteamine is the only topical effective treatment for ocular cystinosis. The lack of investment by the pharmaceutical industry, together with the limited stability of cysteamine, make it available only as two marketed presentations (Cystaran® and Cystadrops®) and as compounding formulations prepared in pharmacy departments. Even so, new drug delivery systems (DDSs) need to be developed, allowing more comfortable dosage schedules that favor patient adherence. In the last decades, different research groups have focused on the development of hydrogels, nanowafers and contact lenses, allowing a sustained cysteamine release. In parallel, different determination methods and strategies to increase the stability of the formulations have also been developed. This comprehensive review aims to compile all the challenges and advances related to new cysteamine DDSs, analytical determination methods, and possible future therapeutic alternatives for treating cystinosis.

Ophthalmic Outcome in a Belgian Cohort of Cystinosis Patients Treated with a Compounded Preparation of Cysteamine Eye Drops: Retrospective Analysis.

IntroductionTreatment of the anterior segment problems in cystinosis is challenging as oral cysteamine is ineffective in the treatment of corneal problems because of its avascular structure. Although cysteamine eye drops have been formulated to counter this issue, the stability of cysteamine in these off-licensed formulations and treatment compliance are major problems. The aim of this retrospective study was to determine the efficacy of a compounded preparation of aqueous 0.5% cysteamine eye drops in the management of corneal complications of cystinosis.MethodsData of patients attending the multidisciplinary cystinosis clinic at the University Hospitals Leuven, Belgium between January 2015 and December 2018 were analyzed. All cystinosis patients were treated with the compounded preparation of aqueous 0.5% cysteamine eye drops and oral cysteamine.ResultsA total of 12 patients were treated with the compounded preparation of aqueous 0.5% cysteamine eye drops, of whom 75% were aged > 18 years (n = 9). The mean instillation frequency of the cysteamine eye drops was 3.3 drops/eye per day, and the mean number of hospital visits was two per year. All patients showed photophobia, > 30% corneal infiltration, blepharospasm, eye pain and conjunctival hyperemia during the study period. None of these symptoms improved with treatment with aqueous compounded 0.5% cysteamine eye drops. The corneal cystine crystal score was ≥ 2 in all patients at the last visit.ConclusionTreatment with the compounded preparation of aqueous 0.5% cysteamine eye drops, combined with oral cysteamine, was not effective in reducing corneal cystine crystal deposition and other ocular symptoms in these patients with cystinosis.FundingRecordati Rare Diseases.

The Ocular Status of Cystinosis Patients Receiving a Hospital Pharmacy-Made Preparation of Cysteamine Eye Drops: A Case Series.

IntroductionInfantile nephropathic cystinosis (INC) is an autosomal recessive lysosomal disorder in which patients develop deposits of cystine crystals in their kidneys and corneas from a young age.MethodsWe conducted a retrospective analysis of children with INC seen by ophthalmologists at the Manchester Royal Eye Hospital between 2002 and 2018, to evaluate clinical findings, symptoms and treatment.ResultsTwenty-two children diagnosed with INC from age 0 (prenatally) to 11 years were assessed. All evaluable patients had corneal cystine crystal deposits, and 15 had mild to moderate photophobia. Ten patients had other ocular conditions including blepharitis/chalzion (n = 6), swollen optic nerve (n = 3), punctate epitheliopathy (n = 3), corneal scarring (n = 1),and elevated intraocular pressure (n = 2). Confocal imaging identified nerve abnormalities in two patients (enlarged corneal nerve + abnormal-looking tortuous nerves in one patient and beaded nerves in the sub-basal plexus in the other), both of whom had significant crystal deposition in the anterior stroma. Visual acuity was relatively unaffected. All 22 patients were receiving oral cysteamine, and 21 were applying cysteamine eye drops (galenic preparation of 0.55% concentration, compounded by a hospital pharmacy). Recommended application frequency was at least eight times per day in all patients with dosing information available.ConclusionsThis case series of patients with INC highlights the consistent pattern of corneal cystine crystal deposition, which is universally present from a young age in this condition, and the high incidence of photophobia even in young children. Corneal manifestations of INC persisted despite frequent administration of the hospital pharmacy-made eye drop preparation. Reasons for this lack of efficacy may include the lag period between diagnosis and first prescription of cysteamine eye drops and the difficulty in maintaining rigorous compliance with this treatment. In addition, the challenge for patients of maintaining optimal storage conditions may adversely affect the stability and efficacy of cysteamine within this preparation.FundingEditorial assistance was funded by Orphan Europe Ltd.

Cysteamine hydrochloride eye drop solution for the treatment of corneal cystine crystal deposits in patients with cystinosis: an evidence-based review.

Cystinosis is a rare, autosomal recessive disorder leading to defective transport of cystine out of lysosomes. Subsequent cystine crystal accumulation can occur in various tissues, including the ocular surface. This review explores the efficacy of cysteamine hydrochloride eye drops in the treatment of corneal cystine crystal accumulation and its safety profile.

In vitro drug release and in vivo safety of vitamin E and cysteamine loaded contact lenses

Cystinosis is an orphan disease caused by a genetic mutation that leads to deposition of cystine crystals in many organs including cornea. Ophthalmic manifestation of the disease can be treated with hourly instillation of cysteamine eye drops. The hourly eye drop instillation is tedious to the patients leading to poor compliance and additionally, significant degradation of the drug occurs within one week of opening the bottle, which further complicates this delivery approach. This paper focuses on designing a contact lens to treat the disease with improved efficacy compared to eye drops, and also exploring safety of the drug eluding contact lens in an animal model. Our goal is to design a lens that is safe and that can deliver a daily therapeutic dose of cysteamine to the cornea while retaining drug stability. We show that cysteamine diffuses out rapidly from all lenses due to its small size. Vitamin E incorporation increases the release duration of both ACUVUE®OASYS® and ACUVUE® TruEyeTM but the effect is more pronounced in TruEyeTM likely due to the low solubility of vitamin E in the lens matrix and higher aspect ratio of the barriers. The barriers are not effective in hydrogel lenses, which along with the high aspect ratio in silicone hydrogels suggests that barriers could be forming at the interface of the silicone and hydrogel phases. The presence of vitamin E has an additional beneficial effect of reduction in the oxidation rates, likely due to a transport barrier between the oxygen diffusing through the silicone channels and drug located in the hydrogel phase. Based on this study, both Acuvue®OASYS® and ACUVUE® TruEyeTM can be loaded with vitamin E to design a cysteamine eluting contact lenses for effective therapy of cystinosis. The lenses must be worn for about 4–5 hr. each day, which is less than the typical duration of daily-wear. The vitamin E and cysteamine loaded lenses did not exhibit any toxicity in a rabbit model over a period of 7-days.

Short-cut diagnostic tool in cystinosis: Bone marrow aspiration.

Cystinosis is a rare metabolic genetic disorder caused by a mutation in cystinosin lysosomal cystine transporter (CTNS). The diagnosis of nephropathic cystinosis (NC) is made by observing corneal cystine crystals and/or measuring the cystine content of leukocytes. CTNS mutation analysis confirms the diagnosis of cystinosis, but leukocyte cystine measurement and CTNS analysis have not been widely available, and cystine crystals in the cornea may not be apparent in the first months of life. Cystine crystal deposition can be seen in the bone marrow earlier than corneal deposition, in patients with NC. Ten patients with cystinosis diagnosis were enrolled in the study. Medical records were reviewed retrospectively to collect demographic and clinical data such as age at diagnosis, disease presentation, parental consanguinity, family history, corneal cystine deposition, leukocyte cystine level, bone marrow cystine deposition, presence of renal failure, follow-up time and prognosis. Cystine crystals were seen in all of the patients' fresh bone marrow aspiration samples. Eight patients had corneal cystine deposition. Leukocyte cystine measurement could have been performed in four patients who had come from another center. Complications such as pulmonary hypertension and idiopathic intracranial hypertension (IIH) were observed in two patients. Bone marrow aspiration might be an easy and short-cut diagnostic tool for NC especially when it is not possible to measure fibroblast cystine content. Additionally some rare complications such as pulmonary hypertension and IIH can be encountered during the course of NC.

Erratum to: Cystadrops® (cysteamine hydrochloride 0.55% viscous eye-drops solution) in treating corneal cystine crystal deposits in patients with cystinosis: a profile of its use

Erratum to: Cystadrops® (cysteamine hydrochloride 0.55% viscous eye-drops solution) in treating corneal cystine crystal deposits in patients with cystinosis: a profile of its use

Cystadrops® (cysteamine hydrochloride 0.55% viscous eye-drops solution) in treating corneal cystine crystal deposits in patients with cystinosis: a profile of its use

Cystadrops® (viscous cysteamine hydrochloride 0.55% eye-drops solution) is the first orphan drug approved in the EU for the treatment of corneal crystal deposits in adults and children aged >2 years with cystinosis. The solution reduced the accumulation of cystine crystals in the cornea and the severity of photophobia in patients of all ages with cystinosis in clinical studies. Instillation adverse effects (e.g. burning and stinging) may occur, but generally are very transient and mild to moderate in severity. Relative to extemporaneously prepared formulations of cysteamine hydrochloride eye drops, Cystadrops® requires less frequent administration (relieving treatment burden), displays better stability (making storage, distribution and use by patients less difficult) and provides reliable standardization and availability.

Efficacy of topical cysteamine in nephropathic cystinosis

PurposeThe aim of this study is to evaluate the efficacy of topical cysteamine 0.55% eye drops in the treatment of corneal cystine crystal deposits in patients with nephropathic cystinosis.MethodsThirty-two patients...

Treatment of corneal cystine crystal accumulation in patients with cystinosis.

Cystinosis is a rare autosomal recessive disorder characterized by the accumulation of cystine within the cells of different organs. Infantile nephropathic cystinosis is the most common and severe phenotype. With the success of renal transplantation, these patients are now living longer and thus more long-term complications within different organs are becoming apparent. Ophthalmic manifestations range from corneal deposits of cystine crystals to pigmentary retinopathy. With increasing age, more severe ocular complications have been reported. Photophobia is a prominent symptom for patients. With prolonged survival and increasing age, this symptom, along with corneal erosions and blepharospasm, can become debilitating. This review revisits the basic pathogenesis of cystinosis, the ocular manifestations of the disease, and the treatment of corneal crystals.

Cystinosis: diagnostic role of bone marrow examination.

The patient was a 1.5-year-old boy who presented with growth failure, inability to walk, polyuria, and polydipsia. On physical examination, he had fair skin and blond hair. He did not have organomegaly. Ophthalmologic examination by an ophthalmologist was normal. Hypophosphatemia, hypovitaminosis D, mild acidosis, glucosuria, proteinuria, and generalized aminoaciduria were found upon laboratory studies. He underwent bone marrow aspiration that revealed increased numbers of macrophages containing polygonal crystals. Severe and widespread deposition of crystals in bone marrow particles (Figure 1) was observed, which was pathognomonic for cystinosis. Cystinosis is a rare autosomal recessive disorder caused by a defect in cystine transport outside the lysosomes, leading to accumulation of cystine crystals in various organs including the kidneys, liver, eyes, and brain [1]. It has 3 forms and infantile nephrophatic cystinosis is the most common and most severe type. Clinical manifestations of this variant include polyuria, polydipsia, dehydration, acidosis, rickets, and failure to thrive due to tubular dysfunction and Fanconi’s syndrome [1,2]. The diagnosis is made by observing corneal cystine crystals and/or measuring the cystine content of leukocytes [1]; however, typical crystals in the bone marrow are diagnostic. Early diagnosis and treatment of these patients can prevent kidney function impairment and other complications secondary to deposition of cystine crystals in various tissues. Informed consent was obtained. Figure 1 Widespread deposition of crystals in bone marrow fragment.

Cysteamine ophthalmic solution 0.44% for the treatment of corneal cystine crystals in cystinosis

Cystinosis is a rare autosomal recessive disease caused by abnormal accumulation of the amino acid cystine within lysosomes of various cells throughout the body, leading to multiple organ damage. Corneal cystine crystals are an ocular manifestation of cystinosis. Untreated, these corneal deposits worsen with time, often resulting in photophobia, ocular discomfort, blurred vision, and in severe cases, recurrent epithelial erosions, and band keratopathy. Oral cysteamine stabilizes renal and other systemic functions in these patients, but has no effect on cystine crystal accumulation in the cornea, due to the absence of a direct blood supply to the cornea. Cysteamine ophthalmic solution 0.44% reduces corneal cystine crystal deposition, helps clear existing crystals and is currently the only US FDA-approved therapy for the treatment of the corneal crystal involvement of cystinosis.

In vivo reflectance confocal microscopy of the skin: A noninvasive means of assessing body cystine accumulation in infantile cystinosis

Patients with infantile nephropathic cystinosis have progressive accumulation of cystine in tissues leading to delayed extrarenal complications. No simple tool is available to evaluate the level of body cystine accumulation. We sought to determine the value of in vivo reflectance confocal microscopy of the skin in patients with infantile nephrogenic cystinosis. Nine patients and control subjects were recruited for this study. Images were acquired by means of a near-infrared reflectance confocal laser scanning microscope. Scattered bright particles within the papillary dermis were observed in all patients but not in control subjects. The density of particles ranged from numerous (+++) to very few (+/-) and their distribution was heterogeneous. Electron microscopy confirmed that these particles corresponded to cystine crystal deposits within dermal fibroblasts. The density of cystine crystals within the dermis was greater in older patients, in patients with a high leukocyte cystine concentration, and with delayed cysteamine therapy. There was no correlation between the density of cystine deposits and renal disease or hypopigmentation but high levels of deposition occurred in association with extrarenal manifestations. This is a preliminary study on a small sample of patients. Repeated examination and longer follow-up is necessary. In vivo reflectance confocal microscopy of the skin appears to be a noninvasive means of assessing body cystine accumulation in infantile cystinosis and could be used as a complementary marker of treatment response in addition to leukocyte cystine measurement.

Cystinosis Presenting with Findings of Bartter Syndrome - Case Report

A five-year-old boy was referred to our pediatric clinic for evaluation of failure to thrive, headache, intermittent high fever, restlessness, polyuria, and polydipsia. His weight and height measurements were under the 3rd percentile. Clinical findings consisted of frontal bossing, carious teeth, O-bain deformity of the lower extremities, and moderate dehydration. The presence of metabolic alkalosis, hypokalemia, hypochloremia, and high renin and aldosterone levels were suggestive of Bartter syndrome and a treatment regimen for Bartter syndrome was started. At follow-up, the polyuria and hyponatremia were found to persist. A reassessment of the patient revealed findings consistent with proximal renal tubular acidosis such as metabolic acidosis with a high urinary pH, proteinuria, aminoaciduria with phosphaturia and hypercalciuria. Based on the presence of parental consanguinity as well as polyuria, proteinuria, low tubular reabsorption of phosphorus, generalized aminoaciduria, light yellow skin and hair color, the probable diagnosis of cystinosis was established and was confirmed by slit-lamp examination of the cornea showing cystine crystal deposition. Our case is a good example demonstrating that development of metabolic alkalosis does not exclude cystinosis and that all findings of the patient should be thoroughly evaluated.Conflict of interest:None declared.

Successful treatment of the murine model of cystinosis using bone marrow cell transplantation

AbstractCystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The defective gene is CTNS encoding the lysosomal cystine transporter, cystinosin. Cystine accumulates in every organ in the body and leads to organ damage and dysfunction, including renal defects. Using the murine model for cystinosis, Ctns−/− mice, we performed syngeneic bone marrow cell (BMC), hematopoietic stem cell (HSC), and mesenchymal stem cell transplantation. Organ-specific cystine content was reduced by 57% to 94% in all organs tested in the BMC-treated mice. Confocal microscopy and quantitative polymerase chain reaction revealed a large quantity of transplanted BMC in all organs tested, from 5% to 19% of the total cells. Most of these cells were not from the lymphoid lineage but part of the intrinsic structure of the organ. The natural progression of renal dysfunction was prevented, and deposition of corneal cystine crystals was significantly improved in the BMC-treated mice. HSC had the same therapeutic effect as whole BMC. In contrast, mesenchymal stem cell did not integrate efficiently in any organ. This work is a proof of concept for using HSC transplantation as a therapy for cystinosis and highlights the efficiency of this strategy for a chronic, progressive degenerative disease.

Cystinosis of the brain and spinal cord with associated vasculopathy

Cystinosis is an autosomal recessive lysosomal storage disease that results in renal failure. CNS manifestations are rare. We report a 29-year man who presented with a cervical myelopathy due to cystinosis. Biopsy of the brain lesions demonstrated cystine crystal deposition and an intense perivascular with inflammatory vasculopathic changes. Symptomatic improvement attended the use of higher doses of cysteamine and corticosteroid therapy. Cystinosis of the nervous system may present as spinal cord disease and be associated with a CNS vasculopathy/vasculitis. As more patients with cystinosis experience long term survival, there will likely be an increased frequency of CNS disease.

Cystinosis, Fanconi syndrome, and odontogenic cysts

Cystinosis is a multisystemic genetic storage disorder characterized by a mutation in the transporter system of cystine. The disease particularly affects the renal system by causing deposition of cystine crystals leading to, if untreated, Fanconi syndrome and end-stage renal disease. This disease also affects the ocular system, central nervous system, endocrine system, hepatobiliary system, and musculoskeletal system. We present the first case of cystine crystal deposition within an odontogenic cyst, confirmed by the correlation of the clinical, radiographic, and histologic findings on this patient.

Glycogénoses, hyperoxaluries, aminoacidopathies et hyperlipidémies

Glycogen storage diseases (GSDs) are inherited disorders that affect glycogen metabolism. The glycogen found in these disorders is abnormal in quantity, quality or both. Liver and muscle have abundant quantities of glycogen and are the most commonly and seriously affected tissues. Because carbohydrate metabolism in the liver is responsible for plasma glucose homeostasis, GSDs that affect mainly the liver usually present as a hepatomegaly and a hypoglycaemia. In contrast, the role of glycogen in muscle is to provide substrates for the generation of ATP for muscle contraction. The predominant clinical features of muscular GSD are muscle cramps, exercise intolerance, susceptibility to fatigue, and progressive weakness. Hyperoxaluria or primary oxalosis is an autosomal recessive disease divided into two forms : type 1, caused by the absence of glyoxylate aminotransferase activity, and type 2 caused by a defect in D-glycerate dehydrogenase/gloxylate reductase. The overproduction of oxalate that is related to these enzyme defect is accompanied by its accumulation in various tissues. Damage to the kidneys, presenting as calcium oxalate nephrolithiasis and nephrocalcinosis, induces progressive renal failure and uraemia treatable by hemodialysis and renal transplantation. Phenylalanine hydroxylase (PAH) deficiency results in an intolerance to dietary intakes of the essential aminoacid phenylalanine and produces a spectrum of disorders including phenylketonuria and non PKU hyperphenylalaninemia. Tyrosinemia encompasses several entities, of which tyrosinemia type 1 (or hepatorenal tyrosinemia) results in the pathological manifestations involving mainly the liver, kidney and peripheral nerves. Classical homocystinuria is an inherited metabolic disorder that arises from defects in either the re-methylation or transsulphuration pathways of homocystein metabolism and leads to skeletal abnormalities, mental retardation and a high risk of vascular disease. Cystinosis is a rare autosomal recessive disorder characterized by the widespread of deposition of cystine crystals in body tissues, particularly in the kidney that results in renal insufficiency treatable by renal transplantation and cysteamine. Familial hypercholesterolemia is characterized by elevated serum cholesterol, tendon xanthomas, xanthelasmas, arcus corneae and premature atherosclerosis. Rheumatological manifestations include acute episodes of polyarthritis and tendinitis. Patients who are homozygous for familial hypercholesterolemia have cardiovascular and rheumatological manifestations more frequently and at earlier age than patients who are heterozygous. Potential myopathy and hepatotoxicity have long been acknowledged as uncommon adverse effects with statins.

The evaluation and treatment of gastrointestinal disease in children with cystinosis receiving cysteamine

Objectives Cysteamine prevents organ damage in children with cystinosis, but may cause gastrointestinal (GI) symptoms. In this study we evaluated the nature of GI disease, and the value of omeprazole in controlling GI symptoms in these children. Study design Upper GI disease was evaluated with endoscopy, gastrin levels, and acid secretion studies after oral administration of cysteamine, before and after 16 weeks of therapy with omeprazole. A symptom score was devised. Results Eleven children (mean age, 5.7 years) were studied. After cysteamine ingestion, before and after omeprazole therapy, the mean maximum acid output was significantly higher than the mean basal acid output. The maximum acid output was measured within 60 minutes of cysteamine ingestion and was reduced by omeprazole therapy ( P<.01). The mean peak gastrin level was 30 minutes postcysteamine and was higher than baseline ( P<.01). The initial mean symptom score (maximum score, 14) was 6.9 and fell to 0.7 ( P<.0001) after 16 weeks of omeprazole therapy. At endoscopy, two children had diffuse gastric nodularity, and nearly all had cystine crystal deposits. Conclusions GI symptoms in children with cystinosis receiving cysteamine are often acid-mediated and improve with omeprazole. Cystine crystals were detected in the GI tract and may signify inadequate treatment with cysteamine.