Search Results (7)

Cystinosis is a rare systemic disease characterized by the accumulation of cystine in tissues, leading to multi-organ damage. Infantile nephropathic cystinosis is the dominant and severe form of cystinosis with critical renal manifestations that require kidney transplantation at an early age if left untreated. Cysteamine, the lifelong cystine-depleting therapy, is the mainstay treatment of nephropathic cystinosis. Cysteamine prevents cystine crystal formation and delays disease progression. While the initially introduced cysteamine consists of an immediate-release (IR) formulation, a delayed-release (DR) formulation has been developed with a simplified dosing regimen (Q12H instead of Q6H) and an improved quality of life while maintaining comparable efficacy. Due to the rare incidence of the disease and lack of international guidelines, diagnosis and treatment initiation are oftentimes delayed, leading to a poor prognosis. Pediatric and adult nephrologists from Kuwait, Saudi Arabia, the United Arab Emirates (UAE), and Qatar, in addition to one international expert from Amsterdam, convened to share their clinical experience, reflecting on the challenges encountered and therapeutic approaches followed in the management of nephropathic cystinosis in the Gulf Cooperation Council (GCC) region. Experts completed a multiple-choice questionnaire and engaged in structured discussions, where they shed light on gaps and limitations with regard to diagnostic tests and criteria to ensure early diagnosis and timely treatment initiation. Based on available literature, experts suggested an algorithm to help guide nephropathic cystinosis management in the GCC. It is highly recommended for patients who do not tolerate IR-cysteamine and do not adhere to IR-cysteamine treatment to switch to DR-cysteamine. Given the systemic nature of the disease, a multi-disciplinary approach is required for optimal disease management. Full article

Cystinosis is an autosomal recessive lysosomal storage disease, caused by mutations in the CTNS gene, resulting in multi-organ cystine accumulation. Three forms of cystinosis are distinguished: infantile and juvenile nephropathic cystinosis affecting kidneys and other organs such as the eyes, endocrine system, muscles, and brain, and adult ocular cystinosis affecting only the eyes. Currently, elevated white blood cell (WBC) cystine content is the gold standard for the diagnosis of cystinosis. We present a patient with proteinuria at adolescent age and corneal cystine crystals, but only slightly elevated WBC cystine levels (1.31 ½ cystine/mg protein), precluding the diagnosis of nephropathic cystinosis. We demonstrate increased levels of cystine in skin fibroblasts and urine-derived kidney cells (proximal tubular epithelial cells and podocytes), that were higher than the values observed in the WBC and healthy control. CTNS gene analysis shows the presence of a homozygous missense mutation (c.590 A > G; p.Asn177Ser), previously described in the Arab population. Our observation underlines that low WBC cystine levels can be observed in patients with juvenile cystinosis, which may delay the diagnosis and timely administration of cysteamine. In such patients, the diagnosis can be confirmed by cystine measurement in slow-dividing cells and by molecular analysis of the CTNS gene. Full article

Manifestations of infantile nephropathic cystinosis (INC) often include cachexia and deficiency of circulating vitamin D metabolites. We examined the impact of 25(OH)D₃ versus 1,25(OH)₂D₃ repletion in Ctns null mice, a mouse model of INC. Six weeks of intraperitoneal administration of 25(OH)D₃ (75 μg/kg/day) or 1,25(OH)₂D₃ (60 ng/kg/day) resulted in Ctns^−/− mice corrected low circulating 25(OH)D₃ or 1,25(OH)₂D₃ concentrations. While 25(OH)D₃ administration in Ctns^−/− mice normalized several metabolic parameters characteristic of cachexia as well as muscle function in vivo, 1,25(OH)₂D₃ did not. Administration of 25(OH)D₃ in Ctns^−/− mice increased muscle fiber size and decreased fat infiltration of skeletal muscle, which was accompanied by a reduction of abnormal muscle signaling pathways. 1,25(OH)₂D₃ administration was not as effective. In conclusion, 25(OH)D₃ supplementation exerts metabolic advantages over 1,25(OH)₂D₃ supplementation by amelioration of muscle atrophy and fat browning in Ctns^−/− mice. Full article

Newborn screening (NBS) programmes are considered to be one of the most successful secondary prevention measures in childhood to prevent or reduce morbidity and/or mortality via early disease identification and subsequent initiation of therapy. However, while many rare diseases can now be detected at an early stage using appropriate diagnostics, the introduction of a new target disease requires a detailed analysis of the entire screening process, including a robust scientific background, analytics, information technology, and logistics. In addition, ethics, financing, and the required medical measures need to be considered to allow the benefits of screening to be evaluated at a higher level than its potential harm. Infantile nephropathic cystinosis (INC) is a very rare lysosomal metabolic disorder. With the introduction of cysteamine therapy in the early 1980s and the possibility of renal replacement therapy in infancy, patients with cystinosis can now reach adulthood. Early diagnosis of cystinosis remains important as this enables initiation of cysteamine at the earliest opportunity to support renal and patient survival. Using molecular technologies, the feasibility of screening for cystinosis has been demonstrated in a pilot project. This review aims to provide insight into NBS and discuss its importance for nephropathic cystinosis using molecular technologies. Full article

Cystinosis Metabolic Bone Disease (CMBD) has emerged during the last decade as a well-recognized, long-term complication in patients suffering from infantile nephropathic cystinosis (INC), resulting in significant morbidity and impaired quality of life in teenagers and adults with INC. Its underlying pathophysiology is complex and multifactorial, associating complementary, albeit distinct entities, in addition to ordinary mineral and bone disorders observed in other types of chronic kidney disease. Amongst these long-term consequences are renal Fanconi syndrome, hypophosphatemic rickets, malnutrition, hormonal abnormalities, muscular impairment, and intrinsic cellular bone defects in bone cells, due to CTNS mutations. Recent research data in the field have demonstrated abnormal mineral regulation, intrinsic bone defects, cysteamine toxicity, muscle wasting and, likely interleukin-1-driven inflammation in the setting of CMBD. Here we summarize these new pathophysiological deregulations and discuss the crucial interplay between bone and muscle in INC. In future, vitamin D and/or biotherapies targeting the IL1β pathway may improve muscle wasting and subsequently CMBD, but this remains to be proven. Full article

Mice lacking the functional cystinosin gene (Ctns^−/−), a model of infantile nephropathic cystinosis (INC), exhibit the cachexia phenotype with adipose tissue browning and muscle wasting. Elevated leptin signaling is an important cause of chronic kidney disease-associated cachexia. The pegylated leptin receptor antagonist (PLA) binds to but does not activate the leptin receptor. We tested the efficacy of this PLA in Ctns^−/− mice. We treated 12-month-old Ctns^−/− mice and control mice with PLA (7 mg/kg/day, IP) or saline as a vehicle for 28 days. PLA normalized food intake and weight gain, increased fat and lean mass, decreased metabolic rate and improved muscle function. It also attenuated perturbations of energy homeostasis in adipose tissue and muscle in Ctns^−/− mice. PLA attenuated adipose tissue browning in Ctns^−/− mice. PLA increased gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in Ctns^−/− mice. This was accompanied by correcting the increased expression of muscle wasting signaling while promoting the decreased expression of myogenesis in gastrocnemius of Ctns^−/− mice. PLA attenuated aberrant expressed muscle genes that have been associated with muscle atrophy, increased energy expenditure and lipolysis in Ctns^−/− mice. Leptin antagonism may represent a viable therapeutic strategy for adipose tissue browning and muscle wasting in INC. Full article

Background: We aimed to identify diagnosed cases of ocular cystinosis and describe clinical, epidemiological and therapeutic characteristics. Methods: This is a descriptive and retrospective case series. All patients underwent a full check-up examination every 4–6 months by ophthalmologists, nephrologists and other required specialists. Results: Of the seven cases, six (85.7%) were females and one (14.2%) was male. The infantile nephropathic form of cystinosis was observed in five patients and the juvenile nephropathic form in two patients. No patients with the ocular form of cystinosis were identified. Corneal cystine crystals (CCC) were found in all analyzed patients. Severe ocular and general complications of the disease that had been standing for years, connected to the infantile nephropathic form, delayed diagnosis or inappropriate treatment, were observed only in two patients. All patients received topical therapy. No adverse events related to the therapy were observed. Conclusions: Cystinosis is a rare, progressive disease. Early diagnosis and treatment prevent serious complications from numerous systemic organs. Patients require constant systematic monitoring by various specialists. Full article