Cystinosis
Brief Summary of Disease
Cystinosis is a rare, heritable disorder characterized by a pathological accumulation of cystine in lysosomes found within the body’s cells.1 Epidemiological surveys have reported low incidence rates of the disorder in countries such as France, Australia, Germany, and Denmark, where these genetic mutations are observed in approximately one of several hundred thousand live births.1 However, researchers have found higher incidence rates of cystinosis in populations where more individuals share a common ancestor.1 For instance, cystinosis has been reported in one out of 62,500 live births in Saguenay-Lac-St-Jean, Quebec, Canada.1
Etiology & Pathology
Cystinosis is an autosomal recessive disease affecting lysosomal storage.1 Lysosomes are enzyme-filled organelles that play a critical role in cell metabolism.2 Specifically, lysosomes allow the cell to process certain materials and recycle them to serve a variety of important biological functions.2 However, in cystinosis, mutations to the CTNS gene causes the cell to produce malfunctioning cystinosin, a protein which normally facilitates the transportation of cystine out of lysosomes across the cell membrane.1 If cystine cannot be transported properly, it can accumulate within the lysosomes, form crystalline precipitates, and cause cellular dysfunction.1 Cystinosis mainly affects renal function, however pathological changes have been observed in the central nervous system, pancreas, thyroid, and eyes.1
“While these symptoms appear as early as six months old, the disease typically becomes more fatal as the accumulation of cystine in tissues progresses.”
Symptoms
There are three separate phenotypes of cystinosis, which includes nephropathic cystinosis, intermediate cystinosis, and non-nephropathic cystinosis.3 Nephropathic cystinosis predominantly affects children, and the disorder is characterized by renal Fanconi syndrome that causes insufficient reabsorption of nutrients in the proximal tubule cells of the kidney.1 If left untreated, nephropathic cystinosis is also characterized by poor growth, short stature, rickets, light sensitivity, abnormal urination, and thirst in children.3 While these symptoms appear as early as six months old, the disease typically becomes more fatal as the accumulation of cystine in tissues progresses.3
Intermediate cystinosis and nephropathic cystinosis share similar clinical manifestations, however intermediate cystinosis is later onset than nephropathic cystinosis.3 Specifically, although there may be some impairment of renal function, individuals with intermediate cystinosis may not develop Fanconi syndrome. 3 It has been suggested that the late-onset phenotype might be a result of mutations to the CTNS gene that do not disrupt the open reading frame of cystinosin. 3 In theory, these differences would cause fewer severe mutations to the protein and might contribute to the late onset of intermediate cystinosis. 3 Finally, non-nephropathic cystinosis, otherwise referred to as ocular cystinosis, is typically caused by the accumulation of cystine in the corneas, contributing to light sensitivity and visual dysfunction.
Diagnosis
Cystinosis can be diagnosed using molecular screening for mutations in the CTNS gene or by assessing the formation of crystals in the cornea with slit lamp examination.1,4 Nonetheless, tests measuring the concentration of cystine in white blood cells have been the most sensitive and specific diagnostic tool for cystinosis1 An assay developed by Oshimo et al. in the 1970s was first used to measure white blood cell concentrations of cystine.5 This assay can examine the competition of non-radioactive cystine, isolated from the patient, with a radioactive isotope of cystine that is generated from E. coli.5 These proteins compete for binding with cystine binding protein, and this radioactivity can be quantified.5 Patient-derived cystine would have no radioactivity when bound to cystine binding protein, meaning that decreases in the signal during the assay allows clinicians to measure the concentration of cystine in the patient sample.5 Although this assay is still used, measuring white blood cell concentrations of cystine have more recently involved technology, such as high-performance liquid chromatography which separates derivatives of cystine from patient samples and quantifies concentrations with a fluorescent signal.1,6
“Advances in diagnosis and treatment of cystinosis have drastically improved the prognosis for individuals with the disease.”
Prognosis
Advances in diagnosis and treatment of cystinosis have drastically improved the prognosis for individuals with the disease.1 Specifically, the development and use of cystine-depleting treatments, dialysis, and kidney transplantation have all helped improve the health outcomes of cystinosis.1 While patients have an increased life expectancy with the availability of these treatments, more long-term complications for the disease are being discovered as individuals with cystinosis age.1 Luckily, cystinosis is being recognized at earlier ages, which has allowed for more timely initiation of cystine-depleting therapy.1 These treatments can significantly prevent and delay complications of the disease, but adherence to the therapy is important to ensuring the best health outcomes for patients.1
“These treatments can significantly prevent and delay complications of the disease, but adherence to the therapy is important to ensuring the best health outcomes for patients.”
Children
Infantile nephropathic cystinosis represents over 95% of cystinosis cases, and it is the most severe form of the disease.1 As mentioned, this phenotype is characterized by renal Fanconi syndrome, which can become progressively worse and lead to end-stage renal failure.1 Therefore, cystine-depleting therapy, which consists of cysteamine treatments, is critical to improving the prognosis for children with cystinosis. Importantly, cysteamine has been shown to delay the progression of end-stage renal disease by 6 to 10 years and prevent other extra-renal complications of the disease.1 Nonetheless, early detection and diagnosis is necessary to achieve optimal health outcomes, considering that cysteamine is most effective when treatments are initiated in infancy and maintained throughout the patient’s life.1
Current Research
Research on cystinosis has largely focused on ways in which treatments can be optimized, however few have focused on identifying a cure for the disease. Dr. Paul Goodyer, Eloxx Pharmaceuticals, and a team of researchers at McGill University in Quebec, Canada are some of the first to try and develop a cure for cystinosis.7 The group have produced a novel aminoglycoside, a type of antibiotic, that can trick the cell to bypass mutations in the CTNS gene, without any long-term toxicity.7 So far, their studies have shown that this compound, ELX-02, is capable of correcting these mutations in patient cells and shows no toxicity in cells, animals, and human volunteers.7 Although the researchers are only in Phase II of their clinical trial, correct production of the normal CTNS protein would present a potential cure for cystinosis.7 This cure would be capable of improving patient life expectancy and quality of life, would save millions of dollars in healthcare expenses, and would set a precedent of a method for treating other genetic disorders caused by nonsense mutations .7
Relevant Resources
For more information, you can refer to the Cystinosis Research Network , an organization that is committed to supporting and advocating cystinosis research, offering assistance to patients and their families, and providing continued education and information to the general public and medical community. If you are interested in becoming involved, the Cystinosis Research Network holds fundraising events, conferences and provides patients with additional resources for cystinosis management and care. Similarly, Cystinosis Awareness and Research Effort (CARE), is the only Canadian organization that works in partnership with the Cystinosis Research Foundation to raise funds and awareness for cystinosis research. CARE also produces videos that highlight individual cases of cystinosis, ongoing research, and other videos that inspire hope for patients and their families.
Works Cited:
1. Elmonem MA, Veys KR, Soliman NA, van Dyck M, van den Heuvel LP, Levtchenko E. Cystinosis: a review. Orphanet J Rare Dis. 2016;11(1):47. doi:10.1186/s13023-016-0426-y
2. Luzio JP, Pryor PR, Bright NA. Lysosomes: fusion and function. Nat Rev Mol Cell Biol. 2007;8:622. http://dx.doi.org/10.1038/nrm2217.
3. Nesterova G, Gahl WA. Cystinosis. GeneReviews. 2001. https://www.ncbi.nlm.nih.gov/books/NBK1400/
4. Wilmer MJ, Schoeber JP, van den Heuvel LP, Levtchenko EN. Cystinosis: practical tools for diagnosis and treatment. Pediatr Nephrol. 2011;26(2):205-215. doi:10.1007/s00467-010-1627-6
5. Oshima RG, Willis RC, Furlong CE, Schneider JA. Binding assays for amino acids. The utilization of a cystine binding protein from Escherichia coli for the determination of acid soluble cystine in small physiological samples. J Biol Chem. 1974;249(19):6033-6039.
6. De Graaf-Hess A, Trijbels F, Blom H. New method for determining cystine in leukocytes and fibroblasts. Clin Chem. 1999;45(12):2224-2228.
7. Novel Aminoglycoside Readthrough Therapy for Nonsense Mutations. Génome Québec. http://www.genomequebec.com/214-en/project/novel-aminoglycoside-readthrough-therapy-for-nonsense-mutations/
Cite This Article:
Hacker A., Chan G., Lewis K., Palczewski K., Ho J. Cystinosis. Illustrated by C Tang. Rare Disease Review. November 2019.
DOI:10.13140/RG.2.2.29021.56803.
