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Cystinosis

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Cystinosis
Other namesCystine storage disease,[1] Abderhalden–Lignac–Kaufmann disease,[2] Abderhalden–Kaufmann–Lignac syndrome
Chemical structure of cystine formed from L-cysteine (under biological conditions)
SpecialtyEndocrinology Edit this on Wikidata

Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine.[3] It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosomal recessive disorder resulting from accumulation of free cystine in lysosomes, eventually leading to intracellular crystal formation throughout the body. Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group. Fanconi syndrome occurs when the function of cells in renal tubules is impaired, leading to abnormal amounts of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium and phosphates.[citation needed]

Cystinosis was the first documented genetic disease belonging to the group of lysosomal storage disease disorders.[4] Cystinosis is caused by mutations in the CTNS gene that codes for cystinosin, the lysosomal membrane-specific transporter for cystine. Intracellular metabolism of cystine, as it happens with all amino acids, requires its transport across the cell membrane. After degradation of endocytosed protein to cystine within lysosomes, it is normally transported to the cytosol. But if there is a defect in the carrier protein, cystine is accumulated in lysosomes. As cystine is highly insoluble, when its concentration in tissue lysosomes increases, its solubility is immediately exceeded and crystalline precipitates are formed in almost all organs and tissues.[5]

However, the progression of the disease is not related to the presence of crystals in target tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are not fully understood. Increased intracellular cystine profoundly disturbs cellular oxidative metabolism and glutathione status,[6] leading to altered mitochondrial energy metabolism, autophagy, and apoptosis.[7]

Cystinosis is usually treated with cysteamine, which is prescribed to decrease intralysosomal cystine accumulation.[8] However, the discovery of new pathogenic mechanisms and the development of an animal model of the disease may open possibilities for the development of new treatment modalities to improve long-term prognosis.[4]

Types

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Symptoms and signs

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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).[citation needed]

Slit-lamp photographs of three-year-old patient with nephropathic cystinosis before (left) and after (right) cysteamine eyedrop therapy. The drops dissolve the crystals in the cornea.

By about age two, cystine crystals may also be present in the cornea. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia). Without treatment, children with cystinosis are likely to experience complete kidney failure by about age ten. With treatment this may be delayed into the patients' teens or 20s. Other signs and symptoms that may occur in patients include muscle deterioration, blindness, inability to swallow, impaired sweating, decreased hair and skin pigmentation, diabetes, and thyroid and nervous system problems.[citation needed]

The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals around age twelve to fifteen. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.[citation needed]

People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.[citation needed]

Crystal morphology and identification

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Cystine crystals are hexagonal in shape and are colorless. They are not found often in alkaline urine due to their high solubility. The colorless crystals can be difficult to distinguish from uric acid crystals which are also hexagonal. Under polarized examination, the crystals are birefringent with a polarization color interference.[9]

Genetics

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Cystinosis has an autosomal recessive pattern of inheritance.

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.[citation needed]

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.[citation needed]

Cystinosis affects approximately 1 in 100,000 to 200,000 newborns.[1] and there are only around 2,000 known individuals with cystinosis in the world [citation needed]. The incidence is higher in the province of Brittany, France, where the disorder affects 1 in 26,000 individuals.[10]

Diagnosis

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Cystinosis is a rare genetic disorder[11] 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.[3]

The accumulation is caused by abnormal transport of cystine from lysosomes, resulting in a massive intra-lysosomal cystine accumulation in tissues. Via an as yet unknown mechanism, lysosomal cystine appears to amplify and alter apoptosis in such a way that cells die inappropriately, leading to loss of renal epithelial cells. This results in renal Fanconi syndrome,[12] 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.[citation needed]

Treatment

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Cystinosis is normally treated with cysteamine, which is available in capsules and in eye drops.[13] 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.[14]

Investigational treatments

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Gene therapy

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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.[15][16][17][18]

CRISPR gene editing

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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:[19][20]

  • Precisely insert repair templates into the genome to restore functional cystinosin.[19]
  • Apply this technology to patient-derived pluripotent stem cells (iPSCs) to create kidney organoids for disease modeling and therapeutic testing, potentially leading to the replacement of defective kidney tubules with healthy, gene-edited ones.[20]

Pharmacological therapies (Beyond Cysteamine)

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Researchers are also investigating novel pharmacological approaches to improve treatment for cystinosis.

  • Cysteamine Prodrugs New formulations of cysteamine, such as prodrugs (inactive compounds metabolized into the active drug in the body), are being developed to improve patient adherence by overcoming the unpleasant smell and taste of existing medications and potentially allowing for less frequent dosing. For example, CF10 is in preclinical development with a Phase 1 clinical trial planned for 2025.[15]
  • Combination Therapies Studies are identifying potential synergistic effects when combining cysteamine with other compounds. For instance, a combination of cysteamine and bicalutamide has shown promise in correcting the proximal tubule phenotype in in vitro models and cystinotic zebrafish, suggesting a novel dual-target pharmacological approach.[21][22]
  • 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.[15]

History

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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.[23][24] 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.[citation needed]

See also

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References

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  1. ^ a b "Cystinosis on Genetic home reference". Archived from the original on 2012-02-10. Retrieved 2011-04-01.
  2. ^ "Abderhalden Kaufmann Lignac syndrome". rarediseases.info.nih.gov. Archived from the original on 15 May 2018. Retrieved 15 May 2018.
  3. ^ a b A. Gahl, William; Jess G. Thoene; Jerry A. Schneider (2002). "Cystinosis". N Engl J Med. 347 (2): 111–121. doi:10.1056/NEJMra020552. PMID 12110740.
  4. ^ a b Nesterova G, Gahl WA. Cystinosis: the evolution of a treatable disease. Pediatr Nephrol 2012;28:51–9.
  5. ^ Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med 2002;347:111-121.
  6. ^ Kumar A, Bachhawat AK. A futile cycle, formed between two ATP-dependent γ-glutamyl cycle enzymes, γ-glutamyl cysteine synthetase and 5-oxoprolinase: the cause of cellular ATP depletion in nephrotic cystinosis?; J Biosci 2010;35:21–25.
  7. ^ Park MA, Thoene JG. Potential role of apoptosis in development of the cystinotic phenotype. Pediatr Nephrol 2005;20:441–446.
  8. ^ Besouw M, Masereeuw R, Van den Heuvel L et al. Cysteamine: an old drug with new potential. Drug Discov Today 2013.
  9. ^ Spencer, Daniel. "Cystine". CRYSTALS. Urinalysis (Texas Collaborative for Teaching Excellence). Archived from the original on 6 November 2016. Retrieved 4 March 2012.
  10. ^ Kalatzis, V; Cherqui S; Jean G; Cordier B; Cochat P; Broyer M; Antignac C (October 2001). "Characterization of a putative founder mutation that accounts for the high incidence of cystinosis in Brittany". J Am Soc Nephrol. 12 (10): 2170–2174. doi:10.1681/ASN.V12102170. PMID 11562417. Archived from the original on 14 February 2015. Retrieved 31 March 2011.
  11. ^ "Cystinosis". Archived from the original on 2011-07-18. Retrieved 2008-07-20.
  12. ^ Howard G. WORTHEN; Robert A. GOOD (1958). "The de Toni-Fanconi Syndrome with Cystinosis". Am J Dis Child. 95 (6): 653–688. doi:10.1001/archpedi.1958.02060050657011. PMID 13532161.
  13. ^ Besouw, Martine; Masereeuw, Rosalinde; Van Den Heuvel, Lambert; Levtchenko, Elena (2013). "Cysteamine: An old drug with new potential". Drug Discovery Today. 18 (15–16): 785–792. doi:10.1016/j.drudis.2013.02.003. PMID 23416144.
  14. ^ Nesterova, Galina; Gahl, William A. (October 6, 2016). "Cystinosis". GeneReviews. University of Washington, Seattle. PMID 20301574. Archived from the original on April 5, 2011. Retrieved January 11, 2017.
  15. ^ a b c "Emerging therapeutic strategies for cystinosis - Frontiers". Frontiers in Pediatrics. 20 May 2025. doi:10.3389/fped.2025.1601409. Retrieved May 28, 2025.
  16. ^ "Phase I/II CYStem clinical trial - Cystinosis Network Europe". Retrieved 2024-05-28.
  17. ^ "DFT383 - Wikipedia". Retrieved 2024-05-28.
  18. ^ "Stem Cell Gene Therapy for Cystinosis - SCGE Platform". Retrieved 2024-05-28.
  19. ^ a b Sendino Garví, E.; Faria, J.; Pou Casellas, C.; Thijssen, S.; Wubbolts, E.J.; Jamalpoor, A.; Harrison, P.; Masereeuw, R.; Janssen, M.J. (2023). "Gene surgery as a potential treatment option for Nephropathic Cystinosis in vitro". doi:10.1101/2023.11.01.565117. Retrieved 2024-05-28.
  20. ^ a b "Stem cell study reveals how infantile cystinosis causes kidney failure – and how to cure it". Retrieved 2024-05-28.
  21. ^ Jamalpoor, A.; Van Gelder, C. A.; Yousef Yengej, F. A.; Zaal, E. A.; Berlingerio, S. P.; Veys, K. R.; Pou Casellas, C.; Voskuil, K.; Essa, K.; Ammerlaan, C. M.; Rega, L. R.; Van Der Welle, R. E.; Lilien, M. R.; Rookmaaker, M. B.; Clevers, H.; Klumperman, J.; Levtchenko, E.; Berkers, C. R.; Verhaar, M. C.; Altelaar, M.; Masereeuw, R.; Janssen, M. J. (2021). "Cysteamine–bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis - PMC - PubMed Central". EMBO Molecular Medicine. 13 (7): e13067. doi:10.15252/emmm.202013067. PMC 8261496. PMID 34165243.
  22. ^ "Novel mechanism for tubular injury in nephropathic cystinosis - eLife". doi:10.7554/eLife.94169. PMID 40111391. Archived from the original on 2025-04-29. Retrieved 2024-05-28.
  23. ^ B.G. Firkin & J.A.Whitworth (1987). Dictionary of Medical Eponyms. Parthenon Publishing. ISBN 1-85070-333-7
  24. ^ "Who Named It?". Archived from the original on 2019-03-01. Retrieved 2024-03-01.
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