Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine.
Cystinosis was the first documented genetic disease belonging to the group of lysosomal storage disease disorders.[Nesterova G, Gahl WA. Cystinosis: the evolution of a treatable disease. Pediatr Nephrol 2012;28:51–9.] 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 endocytosis 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.[Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med 2002;347:111-121.]
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,[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.] leading to altered mitochondrion energy metabolism, autophagy, and apoptosis.[Park MA, Thoene JG. Potential role of apoptosis in development of the cystinotic phenotype. Pediatr Nephrol 2005;20:441–446.]
Cystinosis is usually treated with cysteamine, which is prescribed to decrease intralysosomal cystine accumulation.[Besouw M, Masereeuw R, Van den Heuvel L et al. Cysteamine: an old drug with new potential. Drug Discov Today 2013.] 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.
Types
-
Infantile nephropathic-
-
Adolescent nephropathic-
-
Adult nonnephropathic-
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).
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.
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.
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.
Crystal morphology and identification
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.
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
renal 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.
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.
The accumulation is caused by abnormal transport of cystine from , 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,
Definitive diagnosis and treatment monitoring are most often performed through measurement of white blood cell cystine level using tandem mass spectrometry.
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.
-
Apply this technology to patient-derived pluripotent stem cells (iPSCs) to create Kidney for disease modeling and therapeutic testing, potentially leading to the replacement of defective kidney tubules with healthy, gene-edited ones.
Pharmacological therapies (Beyond Cysteamine)
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.
-
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.
-
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.
History
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.
[B.G. Firkin & J.A.Whitworth (1987). Dictionary of Medical Eponyms. Parthenon Publishing. ] Affected children are developmentally delayed with
dwarfism,
osteomalacia and
osteoporosis. Renal tubular disease is usually present causing aminoaciduria,
glycosuria and
hypokalemia.
Cysteine deposition is most evident in the
conjunctiva and
cornea.
See also
External links
