Cystinosis

• Infantile (classic) nephropathic cystinosis : the most common and severe form, presenting within the first year of life with Fanconi syndrome and rapid progression to renal failure. • Juvenile (intermediate) cystinosis : later onset and slower progression. • Ocular (non-nephropathic or adult) cystinosis : primarily limited to the eyes with minimal or no renal involvement. ==Symptoms and signs==

There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidney problems (sometimes called renal Fanconi syndrome). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis). ==Pathophysiology==

Nephropathic cystinosis is caused by pathogenic variants in the CTNS gene (encoding cystinosin), located on chromosome 17p13, which encodes a lysosomal membrane protein required for cystine transport out of lysosomes. Loss of cystinosin function leads to intralysosomal accumulation of cystine crystals, which cause cellular dysfunction and apoptosis through mechanisms that include oxidative stress and impaired autophagy. The degree of residual cystinosin function correlates with disease severity, accounting for the spectrum from classic infantile to milder forms. ==Diagnosis==

Clinical suspicion: Infants with Fanconi syndrome and failure to thrive; ophthalmologic findings (corneal crystals) support the diagnosis. Measurement of leukocyte cystine levels: the diagnostic biochemical test is elevated cystine concentration in isolated white blood cells (leukocytes). Genetic testing: molecular analysis of CTNS confirms the diagnosis and allows for carrier testing and prenatal diagnosis. Additional testing: renal function and tubular markers, slit-lamp eye exam, thyroid function tests, and assessments for other systemic complications. Complications These complications often develop despite renal replacement therapy: Ocular: corneal cystine crystal deposition causes photophobia, eye irritation, and decreased corneal sensitivity; crystals are visible on slit-lamp examination. Endocrine: hypothyroidism is common; growth hormone deficiency and diabetes mellitus may occur later. Myopathy and swallowing difficulties from progressive proximal muscle weakness and distal involvement in adults. Neurologic: speech delay, cognitive impairment, and ataxia may appear in older children and adults. Other: hepatomegaly, pancreatitis, and gonadal dysfunction have been reported. ==Genetics==

Cystinosis occurs due to a mutation in the gene CTNS, located on chromosome 17, which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profound polyuria (excessive urination), followed by poor growth, photophobia, and ultimately kidney failure by age 6 years in the nephropathic form. All forms of cystinosis (nephropathic, juvenile and ocular) are autosomal recessive, which means that the trait is located on an autosomal chromosome, and only an individual who inherits two copies of the gene – one from both parents – will have the disorder. There is a 25% risk of having a child with the disorder, when both parents are carriers of an autosomal recessive trait. Cystinosis affects approximately 1 in 100,000 to 200,000 newborns. and there are only around 2,000 known individuals with cystinosis in the world . The incidence is higher in the province of Brittany, France, where the disorder affects 1 in 26,000 individuals. ==Diagnosis==

Cystinosis is a rare genetic disorder that causes an accumulation of the amino acid cystine within cells, forming crystals that can build up and damage the cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes. and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease. Definitive diagnosis and treatment monitoring are most often performed through measurement of white blood cell cystine level using tandem mass spectrometry. ==Management==

Current management aims to deplete intracellular cystine, treat renal tubular losses, preserve kidney function, and address systemic complications. Cysteamine therapy: Cysteamine (cysteamine bitartrate) is the only specific disease-modifying therapy. It enters lysosomes and reacts with cystine to form cysteine–cysteamine mixed disulfides that can exit the lysosome via alternative transporters, thereby lowering intralysosomal cystine. Oral cysteamine, started early and given lifelong, markedly reduces leukocyte cystine levels, delays progression to ESKD, and decreases some systemic complications. Both immediate-release and delayed-release formulations are used; adherence and dose optimization are critical. Kidney transplantation: ESKD is managed with renal transplantation when necessary; however, transplantation does not correct systemic cystine accumulation, so cysteamine therapy should be continued after transplant. Ocular treatment: topical cysteamine eye drops reduce corneal crystal burden and symptoms. ==Treatment==

Cystinosis is normally treated with cysteamine, which is available in capsules and in eye drops. Cysteamine acts to solubilize the cystine by (1) forming a mixed disulfide cysteine-cysteamine and (2) reducing cystine to cysteine. People with cystinosis are also often given sodium citrate to treat the blood acidosis, as well as potassium and phosphorus supplements as well as others. If the kidneys become significantly impaired or fail, then treatment must be begun to ensure continued survival, up to and including renal transplantation. ==Investigational treatments==

Gene therapy Gene therapy for cystinosis focuses on replacing the defective CTNS gene, which encodes the lysosomal cystine transporter cystinosin. This approach aims to provide a potentially long-term or curative treatment. • Autologous Hematopoietic Stem Cell Gene Therapy The most advanced gene therapy approach involves collecting a patient's own hematopoietic stem cells (HSCs), modifying them outside the body (ex vivo) to introduce a functional copy of the CTNS gene using a viral vector (e.g., lentivirus), and then reinfusing these modified cells back into the patient after chemotherapy. The modified HSCs are expected to engraft in the bone marrow, produce healthy blood cells, and deliver functional cystinosin throughout the body, thereby reducing cystine accumulation in various tissues. • AVR-RD-04 (now DFT383 by Novartis) This investigational gene therapy, initially developed by AVROBIO in collaboration with the University of California, San Diego (UCSD), has shown promising preliminary results in Phase 1/2 clinical trials. It has received Orphan Drug and Rare Pediatric Disease designations from the FDA. Novartis acquired this program in May 2023 and has initiated a Phase I/II clinical trial (CYStem) recruiting children aged 2–5 years to evaluate its safety and efficacy. CRISPR gene editing CRISPR-Cas9 gene editing technology is being explored to directly correct the defective CTNS gene within a patient's own cells. Research is underway to: • Precisely insert repair templates into the genome to restore functional cystinosin. • Targeting Downstream Pathways Beyond directly reducing cystine accumulation, some therapies are exploring targeting "downstream" pathways or inflammatory mechanisms that contribute to organ damage in cystinosis. ==Prognosis==

Before the invention of cysteamine treatment in the 1970s, most children with classic nephropathic cystinosis reached end-stage chronic kidney disease (ESKD) by 10–12 years of age. With early and continuous cysteamine therapy and modern supportive care, renal survival has improved substantially and many patients survive into adulthood, although they remain at risk for extra-renal complications that affect morbidity. Nevertheless, since cysteamine does not cure, but only slows down the disease progression, in many cases, the first kidney transplant in childhood/adolescence has to be followed by a second kidney transplant only 5–15 years later. ==History==

Cystinosis was first described in the early 20th century by cystine crystal identification in tissues. A historical case of cystinosis was originally termed Abderhalden–Kaufmann–Lignac syndrome (AKL syndrome), also called nephropathic cystinosis, which was observed to be an autosomal recessive renal disorder of childhood comprising cystinosis and renal rickets. It was named for Emil Abderhalden, Eduard Kaufmann and George Lignac. Affected children are developmentally delayed with dwarfism, rickets and osteoporosis. Renal tubular disease is usually present causing aminoaciduria, glycosuria and hypokalemia. Cysteine deposition is most evident in the conjunctiva and cornea. The CTNS gene was identified in the late 1990s, enabling genetic diagnosis and improved understanding of pathogenesis. ==See also==