The aim of this study was to investigate the neuroretinal structure of patients with the lysosomal storage disease cystinosis. In this retrospective cross-sectional analysis, optical coherence tomography (OCT) was used to measure the peripapillary retinal nerve fiber layer (pRNFL), the optic disc volumes, the prelaminar depth and the macular ganglion cell layer volumes (mGCL) in patients with genetically confirmed infantile nephropathic cystinosis. The same measurements were repeated in an age -and spherical equivalent (SE) matched, healthy control group. The cystinosis group included 40 patients (40 eyes) with a mean age of 20.6 ± 8.6 years and a SE of 0.47 ± 1.85. The healthy control group consisted of 30 patients (30 eyes) with a mean age of 20.7 ± 12.5 years and a SE of 0.47 ± 1.29. A pronounced deposition of crystals in the optic disc was observed in all cystinosis cases. Cystine crystals follow the nerve fibers in a dense, pearl-string pattern. A significantly thicker pRNFL and a higher rate of positive prelaminar depth was evident in the cystinosis group (839.7 ± 151.0 μm vs. 775.7 ± 79.6 μm, p = 0.004). A significantly smaller mGCL volume was found in the cystinosis group as compared to normal controls (0.25 ± 0.03 mm³ vs. 0.35 ± 0.03 mm³, p = 0.036). Cystinosis leads to pronounced crystal accumulation in the optic disc in early stages of the disease. This accumulation occurs in concomitance with the well-described cystine crystal deposits in the cornea, which have previously been considered the foremost ocular sign of cystinosis. The pearl-string appearance of crystal deposition suggests a primarily glial localization. A significantly thicker pRNFL and a higher rate of positive prelaminar depth was observed in the OCT scans of cystinosis patients, explaining the clinical impression of a crowded optic disc. Additionally, retinal neurodegeneration was significant in patients with cystinosis if compared to healthy controls. The optic disc crowding may result from the dense deposition of cystine crystals in the optic nerve head and the GCL thinning could be due to metabolically induced ganglion cell atrophy. However, the exact reason for these changes remains to be elucidated.

Cystinosis is a rare genetic disorder, with the majority of patients suffering from infantile nephropathic cystinosis, the most severe form. If left untreated, cystinosis causes serious morbidity, initially through progressive kidney and eye disease, followed by systemic and multiorgan involvement, ultimately leading to premature death. In this systematic review, we summarize the evidence for cystinosis to support the development of an evidence-based clinical practice guideline (SELECT - S3 guideline for cystinosis). We searched MEDLINE, Embase, CENTRAL, CINAHL, and other databases for relevant studies published from 1980 onward. We screened literature dually and independently for eligibility. Primary researchers extracted data, rated the risk of bias of included studies, and rated the certainty of the evidence (CoE). Secondary researchers reviewed for completeness and accuracy. We applied a staggered approach, prioritizing available controlled studies and synthesizing results narratively. We considered 56 studies in our synthesis and assessed findings relevant to 17 of 31 key questions. We identified evidence for 62 of 213 outcomes. Fifty-two outcomes had very low CoE, three low, four moderate, and three high. The moderate and high CoE findings came from indirect comparisons (other chronic multi-organ diseases). There was low evidence that delayed-release cysteamine therapy makes little to no difference on cystine levels compared to immediate-release cysteamine therapy; however, delayed-release cysteamine was associated with a slight increase in adverse events. Starting systemic cysteamine treatment early likely improves renal function compared to a later start. Most included studies lacked a control group, had a high risk of bias, and had a small sample size. Evidence informing the diagnosis and management of cystinosis is limited, with most findings rated as very low certainty. Few direct comparisons involving only individuals with cystinosis yielded low certainty findings, while moderate to high certainty evidence was found only in indirect comparisons. These findings underscore a critical challenge in managing cystinosis: the balancing act of clinical decision-making in the context of lacking evidence. Nonetheless, this systematic review synthesized the best available data for a clinical practice guideline and highlighted specific areas where future research could strengthen the evidence base. The online version contains supplementary material available at 10.1186/s13023-025-03974-z.

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.

Cystinosis metabolic bone disease (CMBD) is an emerging concept in infantile nephropathic cystinosis, patients presenting with bone pains, fractures, and deformations during teenage or early adulthood. The underlying mechanisms remain unclear. Our aim was to explore the pro-inflammatory profile of osteoclastic lineage in cystinotic patients. We obtained blood samples from 14 cystinotic patients and 10 pediatric healthy controls. Peripheral blood mononuclear cells (PBMCs) were isolated and used to explore by RT-qPCR the transcript expression of 8 inflammatory markers (Il-6, Il-8, Il-1β, CXCL1, CCL2/MCP-1, CXCR3, Il-1 Receptor, Il-6 Receptor). In addition, when possible, PBMCs were differentiated into osteoclasts for further experiments. The expression of Il-6, IL-8, CXCR3, and CCL2/MCP-1 was significantly increased in PBMCs from cystinotic patients. We also explored the expression of Il-1 Receptor and Il-6 Receptor, two major pro-osteoclastic signal inducers, in osteoclasts differentiated from PBMCs from controls (N = 3) and patients (N = 4). The expression of IL-1 Receptor (but not IL-6 receptor) was increased in osteoclasts obtained from cystinotic patients. There is an inflammatory profile in PBMCs and osteoclastic lineage in cells obtained from cystinotic patients. CXCR3 and MCP-1 stimulate migration and activation of macrophages, that may explain the previously reported local increased osteoclastogenesis. The osteoclastic overexpression of IL-1 Receptor is a relevant observation in the field since blocking Il-1β signaling has recently been proposed as a novel therapeutic approach to improve muscular wasting in this orphan disease. • Cystinosis metabolic bone disease (CMBD), an emerging concept with unclear underlying mechanisms, induces bone pains, fractures and deformations in patients with cystinosis. • Blocking Il-1β signaling may be a novel therapeutic approach to improve muscular wasting in cystinosis. • There is an inflammatory profile in PBMCs and osteoclastic lineage in cells obtained from cystinotic patients, with an over-expression of IL-1 Receptor in osteoclasts. • We provide another experimental rationale to propose targeted anti-inflammatory therapies in cystinotic patients with severe bone disease.