Wikipedia

Cystinosis

Cystinosisis alysosomal storage diseasecharacterized by the abnormal accumulation ofcystine,the oxidized dimer of theamino acidcysteine.[3]It is agenetic disorderthat follows anautosomal recessiveinheritancepattern. It is a rare autosomal recessive disorder resulting from accumulation of free cystine inlysosomes,eventually leading to intracellular crystal formation throughout the body. Cystinosis is the most common cause ofFanconi syndromein the pediatric age group. Fanconi syndrome occurs when the function of cells inrenal tubulesis impaired, leading to abnormal amounts ofcarbohydratesand amino acids in theurine,excessive urination, and low blood levels ofpotassiumandphosphates.[citation needed]

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

Cystinosis was the first documented genetic disease belonging to the group of lysosomal storage disease disorders.[4]Cystinosis is caused by mutations in theCTNSgene 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 ofendocytosedprotein to cystine within lysosomes, it is normally transported to thecytosol.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 oxidativemetabolismandglutathionestatus,[6]leading to alteredmitochondrialenergy metabolism,autophagy,andapoptosis.[7]

Cystinosis is usually treated withcysteamine,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 particularkidneyproblems (sometimes called renalFanconi 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 thecornea.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,andthyroidandnervous systemproblems.[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 geneCTNS,located onchromosome 17,which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profoundpolyuria(excessive urination), followed by poor growth,photophobia,and ultimatelykidney failureby age 6 years in the nephropathic form.[citation needed]

All forms of cystinosis (nephropathic, juvenile and ocular) areautosomal 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 ofBrittany,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 theamino acidcystinewithin 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 fromlysosomes,resulting in a massive intra-lysosomal cystine accumulation in tissues. Via an as yet unknown mechanism, lysosomal cystine appears to amplify and alterapoptosisin such a way that cells die inappropriately, leading to loss of renal epithelial cells. This results in renalFanconi 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 withcysteamine,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 givensodium citrateto 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 includingrenal transplantation.[14]

History

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A historical case of cystinosis was originally termedAbderhalden–Kaufmann–Lignac syndrome(AKL syndrome), also callednephropathic cystinosis,which was observed to be anautosomal recessiverenal disorder of childhood comprising cystinosis and renalrickets.It was named forEmil Abderhalden,Eduard KaufmannandGeorge Lignac.[15][16]Affected children are developmentally delayed withdwarfism,ricketsandosteoporosis.Renal tubular disease is usually present causingaminoaciduria,glycosuriaandhypokalemia.Cysteinedeposition is most evident in theconjunctivaandcornea.[citation needed]

See also

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References

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  1. ^ab"Cystinosis on Genetic home reference".
  2. ^"Abderhalden Kaufmann Lignac syndrome".rarediseases.info.nih.gov.Archived fromthe originalon 15 May 2018.Retrieved15 May2018.
  3. ^abA. Gahl, William; Jess G. Thoene; Jerry A. Schneider (2002). "Cystinosis".N Engl J Med.347(2): 111–121.doi:10.1056/NEJMra020552.PMID12110740.
  4. ^abNesterova 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).Retrieved4 March2012.
  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.PMID11562417.Retrieved31 March2011.
  11. ^"Cystinosis".Archived fromthe originalon 2011-07-18.Retrieved2008-07-20.
  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.PMID13532161.
  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.PMID23416144.
  14. ^Nesterova, Galina; Gahl, William A. (October 6, 2016)."Cystinosis".GeneReviews.University of Washington, Seattle.PMID20301574.
  15. ^B.G. Firkin & J.A.Whitworth (1987).Dictionary of Medical Eponyms.Parthenon Publishing.ISBN1-85070-333-7
  16. ^Who Named It?
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