Cystinosis: a review

Mohamed A Elmonem, Koenraad R Veys, Neveen A Soliman, Maria van Dyck, Lambertus P van den Heuvel, Elena Levtchenko, Mohamed A Elmonem, Koenraad R Veys, Neveen A Soliman, Maria van Dyck, Lambertus P van den Heuvel, Elena Levtchenko

Abstract

Cystinosis is the most common hereditary cause of renal Fanconi syndrome in children. It is an autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene encoding for the carrier protein cystinosin, transporting cystine out of the lysosomal compartment. Defective cystinosin function leads to intra-lysosomal cystine accumulation in all body cells and organs. The kidneys are initially affected during the first year of life through proximal tubular damage followed by progressive glomerular damage and end stage renal failure during mid-childhood if not treated. Other affected organs include eyes, thyroid, pancreas, gonads, muscles and CNS. Leucocyte cystine assay is the cornerstone for both diagnosis and therapeutic monitoring of the disease. Several lines of treatment are available for cystinosis including the cystine depleting agent cysteamine, renal replacement therapy, hormonal therapy and others; however, no curative treatment is yet available. In the current review we will discuss the most important clinical features of the disease, advantages and disadvantages of the current diagnostic and therapeutic options and the main topics of future research in cystinosis.

Figures

Fig. 1
Fig. 1
Schematic representation of the CTNS gene and all reported mutations in cystinosis patients. Exonic mutations are displayed in the lower half of the figure, while promoter and intronic mutations and large deletions are displayed in the upper half. INC: infantile nephropathic cystinosis, JNC: juvenile nephropathic cystinosis, OC: ocular cystinosis
Fig. 2
Fig. 2
Typical growth charts in 2 cystinosis patients: a- Normal growth pattern at birth, followed by decreased growth velocity after six months. b- Progressive decrease in growth velocity in a patient who started cysteamine therapy after 2 years of age and was not treated with GH. Green and blue lines represent the 3rd and the 97th percentiles for Height and weight, respectively. (Adapted with permission from Besouw and Levtchenko, 2010) [27]
Fig. 3
Fig. 3
Rickets in cystinosis. a- A cystinosis child with evident rachitic bone deformities. b- Active rachitic bone disease in X-Rays
Fig. 4
Fig. 4
Corneal cystine crystals. Slit lamp examination of corneal cystine deposits (courtesy of Prof. Dr. Akmal Rizk, Dr. Mohamed Gamal and Prof. Dr. Neveen Soliman)
Fig. 5
Fig. 5
The effect of cysteamine treatment in two siblings with nephropathic cystinosis. The growth in the 30-months old younger sibling (right side, 86 cm, 11.5 kg) who received pre-symptomatic cysteamine therapy at 3 months of age exceeded that of his 56-months old elder brother (left side, 80 cm, 10.5 kg) with later diagnosis and treatment at the age of 20 months (courtesy of Dr. Rasha Helmy and Prof. Dr. Neveen Soliman)

References

    1. Abderhalden E. Familiare cystindiathese. Z Physiol Chem. 1903;38:557–61. doi: 10.1515/bchm2.1903.38.5-6.557.
    1. Lignac GOE. Uber storung des cystinstoffwechsels bei kindern. Deutsch Arch Klin Med. 1924;145:139–50.
    1. Fanconi G. Die nicht diabetischen glykosurien und hyperglykaemien des aelteren kindes. Jb Kinderheilk. 1931;133:257–300.
    1. Nesterova G, Gahl WA. Cystinosis: the evolution of a treatable disease. Pediatr Nephrol. 2013;28:51–9. doi: 10.1007/s00467-012-2242-5.
    1. Thoene JG, Oshima RG, Crawhall JC, Olson DL, Schneider JA. Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo. J Clin Invest. 1976;58:180–9. doi: 10.1172/JCI108448.
    1. Liu B, Du H, Rutkowski R, Gartner A, Wang X. LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science. 2012;337:351–354. doi: 10.1126/science.1220281.
    1. Jézégou A, Llinares E, Anne C, Kieffer-Jaquinod C, O’Regan S, Aupetit J, Chabli A, Sagné C, Debacker C, Chadefaux-Vekemans B, Journet A, André B, Gasnier B. Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy. Proc Natl Acad Sci U S A. 2012;109:E3434–43. doi: 10.1073/pnas.1211198109.
    1. Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347:111–21. doi: 10.1056/NEJMra020552.
    1. Cochat P, Cordier B, Lacote C, Said M-H. Cystinosis: Epidemiology in France. In: Broyer M, editor. Cystinosis. Paris: Elsevier; 1999. pp. 28–35.
    1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–54. doi: 10.1001/jama.281.3.249.
    1. Manz F, Gretz N. Cystinosis in the Federal Republic of Germany. J Inherit Metab Dis. 1985;8:2–4. doi: 10.1007/BF01805472.
    1. Ebbesen F, Mygind KI, Holck F. Infantile nephropathic cystinosis in Denmark. Danish Med Bull. 1976;23:216–22.
    1. Hult M, Darin N, von Döbeln U, Månsson JE. Epidemiology of lysosomal storage diseases in Sweden. Acta Paediatr. 2014;103:1258–63. doi: 10.1111/apa.12807.
    1. Bois E, Feingold J, Frenay P, Briard ML. Infantile cystinosis in France: genetics, incidence, geographic distribution. J Med Genet. 1976;13:434–8. doi: 10.1136/jmg.13.6.434.
    1. De Braekeleer M. Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada) Hum Hered. 1991;41:141–6. doi: 10.1159/000153992.
    1. Hutchesson AC, Bundey S, Preece MA, Hall SK, Green A. A comparison of disease and gene frequencies of inborn errors of metabolism among different ethnic groups in the West Midlands. UK J Med Genet. 1998;35:366–70. doi: 10.1136/jmg.35.5.366.
    1. Elmonem MA, Mahmoud IG, Mehaney DA, Sharaf SA, Hassan SA, Orabi A, Salem F, Girgis MY, El-Badawy A, Abdelwahab M, Salah Z, Soliman NA, Hassan FA, Selim LA. Lysosomal storage disorders in Egyptian children. Ind J Pediatr. 2016
    1. Levtchenko E, van den Heuvel L, Emma F, Antignac C. Clinical utility gene card for: cystinosis. Eur J Hum Genet. 2014;22(5).
    1. Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA. CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet. 1998;63:1352–62. doi: 10.1086/302118.
    1. Soliman NA, Elmonem MA, van den Heuvel L, Abdel Hamid RH, Gamal M, Bongaers I, Marie S, Levtchenko E. Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis. JIMD Rep. 2014;14:87–97. doi: 10.1007/8904_2013_288.
    1. Schnaper HW, Cottel J, Merrill S, Marcusson E, Kissane JM, Schackelford GD, So SK, Nelson RD, Cole BR, Smith ML. Early occurence of end-stage renal disease in a patient with infantile cystinosis. J Pediatr. 1992;120:575–8. doi: 10.1016/S0022-3476(05)82486-2.
    1. Long WS, Seashore MR, Siegel NJ, Bia MJ. Idiopathic Fanconi Syndrome with progressive renal failure: a case report and discussion. Yale J Biol Med. 1990;63:15–28.
    1. Brodehl J, Hagge W, Gellisen K. Changes in kidney function in cystinosis. I. Inulin, PAH and electrolyete clearance in various stages of the disease. Ann Paediatr. 1965;205:131–54.
    1. Baum M. The fanconi syndrome of cystinosis: insights into the pathophysiology. Pediatr Nephrol. 1998;12:492–7. doi: 10.1007/s004670050495.
    1. Roth KS, Foreman JW, Segal S. The Fanconi syndrome and mechanisms of tubular transport dysfunction. Kidney Int. 1981;20:705–16. doi: 10.1038/ki.1981.200.
    1. Gaide Chevronnay HP, Janssens V, Van Der Smissen P, N’Kuli F, Nevo N, Guiot Y, Levtchenko E, Marbaix E, Pierreux CE, Cherqui S, Antignac C, Courtoy PJ. Time course of pathogenic and adaptation mechanisms in cystinotic mouse kidneys. J Am Soc Nephrol. 2014;25:1256–1269. doi: 10.1681/ASN.2013060598.
    1. Wilmer MJ, Schoeber JP, van den Heuvel LP, Levtchenko EN. Cystinosis: practical tools for diagnosis and treatment. Pediatr Nephrol. 2011;26:205–15. doi: 10.1007/s00467-010-1627-6.
    1. O’Regan S, Mongeau JG, Robitaille P. A patient with cystinosis presenting with the features of Bartter syndrome. Acta Paediatr Belg. 1980;33:51–2.
    1. Ozkan B, Cayir A, Kosan C, Alp H. Cystinosis presenting with findings of barter syndrome. J Clin Res Pediatr Endocrinol. 2011;3:101–4. doi: 10.4274/jcrpe.v3i2.21.
    1. Gahl WA, Reed GF, Thoene JG, Schulman JD, Rizzo WB, Jonas AJ. Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med. 1987;316:971–7. doi: 10.1056/NEJM198704163161602.
    1. Besouw M, Levtchenko E. Growth retardation in children with cystinosis. Minerva Pediatr. 2010;62:307–14.
    1. Theodoropoulos DS, Shawker TH, Heinrichs C, Gahl WA. Medullary nephrocalcinosis in nephropathiccystinosis. Pediatr Nephrol. 1995;9:412–8. doi: 10.1007/BF00866713.
    1. Betend B, Chatelain P, David L, François R. Treatment of rickets caused by infantile cystinosis using 1 alpha-hydroxy vitamin D. Arch Fr Pediatr. 1982;39:615–8.
    1. Wilmer MJ, Christensen EI, van den Heuvel LP, Monnens LA, Levtchenko EN. Urinary protein excretion pattern and renal expression of megalin and cubilin in nephropathic cystinosis. Am J Kidney Dis. 2008;51:893–903. doi: 10.1053/j.ajkd.2008.03.010.
    1. Gretz N, Manz F, Augustin R, Barrat TM, Bender-Götze C, Brandis M. Survival time in cystinosis: a collaborative study. Proc Eur Dial Transplant Assoc. 1983;19:582–9.
    1. Brodin Sartorius A, Tete MJ, Niaudet P, Antignac C, Guest G, Ottolenghi C, Charbit M, Moyse D, Legendre C, Lesavre P, Cochat P, Servais A. Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults. Kidney Int. 2012;81:179–89. doi: 10.1038/ki.2011.277.
    1. Middleton R, Bradbury M, Webb N, O’Donoghue D, van’t Hoff W. Cystinosis. A clinico-pathological conference. “from toddlers to twenties and beyond” adult-paediatric nephrology interface meeting, Manchester 2001. Nephrol Dial Transplant. 2003;18:2492–5. doi: 10.1093/ndt/gfg445.
    1. Servais A, Morinière V, Grünfeld JP, Noël LH, Goujon JM, Chadefaux-Vekemans B, Antignac C. Late-onset nephropathic cystinosis: clinical presentation, outcome, and genotyping. Clin J Am Soc Nephrol. 2008;3:27–35. doi: 10.2215/CJN.01740407.
    1. Anikster Y, Lucero C, Guo J, Huizing M, Shotelersuk V, Bernardini I, McDowell G, Iwata F, Kaiser-Kupfer MI, Jaffe R, Thoene J, Schneider JA, Gahl WA. Ocular non-nephropathic cystinosis: clinical, biochemical, and molecular correlations. Pediatr Res. 2000;47:17–23. doi: 10.1203/00006450-200001000-00007.
    1. Nesterova G, Gahl WA. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol. 2008;23:863–7. doi: 10.1007/s00467-007-0650-8.
    1. Kaiser-Kupfer MI, Caruso RC, Minkler DS, Gahl WA. Long-term ocular manifestations in nephropathic cystinosis. Arch Ophtalmol. 1986;104:706–11. doi: 10.1001/archopht.1986.01050170096030.
    1. Tsilou ET, Rubin BI, Reed GF, Iwata F, Gahl W, Kaiser-Kupfer MI. Age-related prevalence of anterior segment complications in patients with infantile nephropathic cystinosis. Cornea. 2006;21:173–6. doi: 10.1097/00003226-200203000-00009.
    1. Tsilou ET, Rubin BI, Reed G, Caruso RS, Iwata F, Balog J, Gahl WA, Kaiser-Kupfer MI. Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy. Ophtalmology. 2006;113:1002–9. doi: 10.1016/j.ophtha.2005.12.026.
    1. Gahl WA, Kuehl EM, Iwata F, Lindblad A, Kaiser-Kupfer MI. Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eye drops. Mol Genet Metab. 2000;71:100–20. doi: 10.1006/mgme.2000.3062.
    1. Chan AM, Lynch MJG, Bailey JD, Ezrin C, Fraser D. Hypothyroidism in cystinosis. A clinical, endocrinologic and histologic study involving sixteen patients with cystinosis. Am J Med. 1970;48:678–92. doi: 10.1016/S0002-9343(70)80002-X.
    1. Grünebaum M, Lebowitz RL. Hypothyroidism in cystinosis. Am J Roentgenol. 1977;129:629–30. doi: 10.2214/ajr.129.4.629.
    1. Gaide Chevronnay HP, Janssens V, Van Der Smissen P, Liao XH, Abid Y, Nevo N, Antignac C, Refetoff S, Cherqui S, Pierreux CE, Courtoy PJ. A mouse model suggests two mechanisms for thyroid alterations in infantile cystinosis: decreased thyroglobulin synthesis due to endoplasmic reticulum stress/unfolded protein response and impaired lysosomal processing. Endocrinology. 2015;156:2349–64. doi: 10.1210/en.2014-1672.
    1. Gahl WA, Schneider JA, Thoene JG, Chesney R. The course of nephropathic cystinosis after age 10 years. J Pediatr. 1986;109:605–8. doi: 10.1016/S0022-3476(86)80221-9.
    1. Fivush B, Green OC, Porter CC, Balfe JW, O’Regan S, Gahl WA. Pancreatic endocrine insufficiency in post-transplant cystinosis. Am J Dis Child. 1987;141:1087–9.
    1. Filler G, Amendt P, von Bredow MA, Rohde W, Ehrich JH. Slowly deteriorating insulin secretion and C-peptide production characterizes diabetes mellitus in infantile cystinosis. Eur J Pediatr. 1998;157:738–42. doi: 10.1007/s004310050926.
    1. Fivush B, Flick JA, Gahl WA. Pancreatic exocrine insufficiency in a patient with nephropathic cystinosis. J Pediatr. 1998;112:49–51. doi: 10.1016/S0022-3476(88)80119-7.
    1. Winkler L, Offner G, Krull F, Brodehl J. Growth and pubertal development in nephropathic cystinosis. Eur J Pediatr. 1993;152:244–9. doi: 10.1007/BF01956154.
    1. Chik CL, Friedman A, Merriam GR, Gahl WA. Pituitary testicular function in nephropathiccystinosis. Ann Intern Med. 1993;119:568–75. doi: 10.7326/0003-4819-119-7_Part_1-199310010-00004.
    1. Besouw MT, Kremer JA, Janssen MC, Levtchenko EN. Fertility status in male cystinosis patients treated with cysteamine. Fertil Steril. 2010;93:1880–3. doi: 10.1016/j.fertnstert.2008.12.113.
    1. Reiss RE, Kuwabara T, Smith ML, Gahl WA. Succesful pregnancy despite placental cystine crystals in a woman with nephropathic cystinosis. N Engl J Med. 1988;319:223–6. doi: 10.1056/NEJM198807283190406.
    1. Fink JK, Brouwers P, Barton N, Malekzadeh MH, Sato S, Hill S, Cohen WE, Fivush B, Gahl WA. Neurologic complications in long-standing nephropathic cystinosis. Arch Neurol. 1989;46:543–8. doi: 10.1001/archneur.1989.00520410077027.
    1. Broyer M, Tete MJ, Guest G, Bertheleme JP, Labrousse F, Poisson M. Clinical polymorphism of cystinosis encephalopathy. Results of treatment with cysteamine. J Inherit Metab Dis. 1996;19:65–75. doi: 10.1007/BF01799350.
    1. Nichols SL, Press GA, Schneider JA, Trauner DA. Cortical atrophy and cognitive performance in infantile nephropathic cystinosis. Pediatr Neurol. 1990;6:379–81. doi: 10.1016/0887-8994(90)90004-K.
    1. Trauner DA, Chase C, Scheller J, Katz B, Schneider JA. Neurologic and cognitive deficits in children with cystinosis. J Pediatr. 1988;112:912–4. doi: 10.1016/S0022-3476(88)80214-2.
    1. Dogulu CF, Tsilou E, Rubin B, Fitsgibbon EJ, Kaiser-Kupfer MI, Rennert OM, Gahl WA. Idiopathic Intracranial hypertension in cystinosis. J Pediatr. 2004;145:673–8. doi: 10.1016/j.jpeds.2004.06.080.
    1. Delgado G, Schatz A, Nichols S, Appelbaum M, Trauner D. Behavioral profiles of children with infantile nephropathic cystinosis. Dev Med Child Neurol. 2004;47:403–7. doi: 10.1017/S0012162205000782.
    1. Besouw MT, Hulstijn-Dirkmaat GM, van der Rijken RE, Cornelissen EA, van Dael CM, Vande Walle J, Lilien MR, Levtchenko EN. Neurocognitive functioning in school-aged cystinosis patients. J Inherit Metab Dis. 2010;33:787–93. doi: 10.1007/s10545-010-9182-7.
    1. Bava S, Theilmann RJ, Sach M, May SJ, Frank LR, Hesselink JR, Vu D, Trauner DA. Developmental changes in cerebral white matter microstructure in a disorder of lysosomal storage. Cortex. 2010;46:206–16. doi: 10.1016/j.cortex.2009.03.008.
    1. Gahl WA, Dalakas MC, Charnas L, Chen KT, Pezeshkpour GH, Kuwabara T. Myopathy and cystine storage in muscles in a patient with nephropathic cystinosis. N Engl J Med. 1988;319:1461–4. doi: 10.1056/NEJM198812013192206.
    1. Vester U, Schubeter M, Offner G, Brodehl J. Distal myopathy in nephropathic cystinosis. Pediatr Nephrol. 2000;14:36–8. doi: 10.1007/s004670050009.
    1. Anikster Y, Lacbawan F, Brantly M, Gochuico BL, Avila NA, Travis W, Gahl WA. Pulmonary dysfunction in adults with nephropathic cystinosis. Chest. 2001;119:394–401. doi: 10.1378/chest.119.2.394.
    1. Sonies BC, Almajid P, Kleta R, Bernardini I, Gahl WA. Swallowing dysfunction in 101 patients with nephropathic cystinosis – benefit of long-term cysteamine therapy. Medicine. 2005;84:137–46. doi: 10.1097/01.md.0000164204.00159.d4.
    1. Guillet G, Sassolas B, Fromentoux S, Gobin E, Leroy JP. Skin storage of cystine and premature skin ageing in cystinosis. Lancet. 1998;352:1444–5. doi: 10.1016/S0140-6736(05)61267-6.
    1. Chiaverini C, Sillard L, Flori E, Ito S, Briganti S, Wakamatsu K, Fontas E, Berard E, Cailliez M, Cochat P, Foulard M, Guest G, Niaudet P, Picardo M, Bernard FX, Antignac C, Ortonne JP, Ballotti R. Cystinosin is a melanosomal protein that regulates melanin synthesis. FASEB J. 2012;26:3779–89. doi: 10.1096/fj.11-201376.
    1. 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;249:6033–9.
    1. de Graaf-Hess A, Trijbels F, Blom H. New method for determining cystine in leukocytes and fibroblasts. Clin Chem. 1999;45:2224–8.
    1. Chabli A, Aupetit J, Raehm M, Ricquier D, Chadefaux-Vekemans B. Measurement of cystine in granulocytes using liquid chromatography-tandem mass spectrometry. Clin Biochem. 2007;40:692–8. doi: 10.1016/j.clinbiochem.2007.02.005.
    1. Elmonem MA, Makar SH, van den Heuvel L, Abdelaziz H, Abdelrahman SM, Bossuyt X, Janssen MC, Cornelissen EA, Lefeber DJ, Joosten LA, Nabhan MM, Arcolino FO, Hassan FA, Gaide Chevronnay HP, Soliman NA, Levtchenko E. Clinical utility of chitotriosidase enzyme activity in nephropathic cystinosis. Orphanet J Rare Dis. 2014;9:155. doi: 10.1186/s13023-014-0155-z.
    1. Taranta A, Wilmer MJ, van den Heuvel LP, Bencivenga P, Bellomo F, Levtchenko EN, Emma F. Analysis of CTNS gene transcripts in nephropathic cystinosis. Pediatr Nephrol. 2010;25:1263–7. doi: 10.1007/s00467-010-1502-5.
    1. Soliman NA, El-Baroudy R, Rizk A, Bazaraa H, Younan A. Nephropathic cystinosis in children: An overlooked disease. Saudi J Kidney Dis Transpl. 2009;20:436–42.
    1. Chiavérini C, Kang HY, Sillard L, Berard E, Niaudet P, Guest G, Cailliez M, Bahadoran P, Lacour JP, Ballotti R, Ortonne JP. In vivo reflectance confocal microscopy of the skin: a noninvasive means of assessing body cystine accumulation in infantile cystinosis. J Am Acad Dermatol. 2013;68:e111–6. doi: 10.1016/j.jaad.2011.08.010.
    1. Besouw MT, Van Dyck M, Cassiman D, Claes KJ, Levtchenko EN. Management dilemmas in pediatric nephrology: Cystinosis. Pediatr Nephrol. 2015
    1. Wamelink MM, Struys EA, Jansen EE, Blom HJ, Vilboux T, Gahl WA, Kömhoff M, Jakobs C, Levtchenko EN. Elevated concentrations of sedoheptulose in bloodspots of patients with cystinosis caused by the 57-kb deletion: implications for diagnostics and neonatal screening. Mol Genet Metab. 2011;102:339–42. doi: 10.1016/j.ymgme.2010.12.002.
    1. Heil SG, Levtchenko E, Monnens LA, Trijbels FJ, Van der Put NM, Blom HJ. The molecular basis of Dutch infantile nephropathic cystinosis. Nephron. 2001;89:50–5. doi: 10.1159/000046043.
    1. Kiehntopf M, Varga RE, Koch HG, Beetz C. A homemade MLPA assay detects known CTNS mutations and identifies a novel deletion in a previously unresolved cystinosis family. Gene. 2012;495:89–92. doi: 10.1016/j.gene.2011.12.005.
    1. Bendavid C, Kleta R, Long R, Ouspenskaia M, Muenke M, Haddad BR, Gahl WA. FISH diagnosis of the common 57-kb deletion in CTNS causing cystinosis. Hum Genet. 2004;115:510–4. doi: 10.1007/s00439-004-1170-2.
    1. States B, Blazer B, Harris D, Segal S. Prenatal diagnosis of cystinosis. J Pediatr. 1975;87:558–62. doi: 10.1016/S0022-3476(75)80820-1.
    1. Jackson M, Young E. Prenatal diagnosis of cystinosis by quantitative measurement of cystine in chorionic villi and cultured cells. Prenat Diagn. 2005;25:1045–7. doi: 10.1002/pd.1249.
    1. Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wühl E, Niaudet P, Van’t Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014;29:iv87–iv94. doi: 10.1093/ndt/gfu090.
    1. Loirat C. Symptomatic therapy. In: Broyer M, editors. Cystinosis, 1st edn Elsevier; Paris: 1999.pp.97–102.
    1. Cochat P, Pichault V, Bacchetta J, Dubourg L, Sabot JF, Saban C, Daudon M, Liutkus A. Nephrolithiasis related to inborn metabolic diseases. Pediatr Nephrol. 2010;25:415–24. doi: 10.1007/s00467-008-1085-6.
    1. Gahl WA, Bernardini I, Dalakas M, Rizzo WB, Harper GS, Hoeg JM, Hurko O, Bernar J. Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome. J Clin Invest. 1988;81:549–60. doi: 10.1172/JCI113353.
    1. Gahl WA, Bernardini IM, Dalakas MC, Markello TC, Krasnewich DM, Charnas LR. Muscle carnitine repletion by long-term carnitine supplementation in nephropathic cystinosis. Pediatr Res. 1993;34:115–9. doi: 10.1203/00006450-199308000-00001.
    1. Elenberg E, Norling LL, Kleinman RE, Ingelfinger JR. Feeding problems in cystinosis. Pediatr Nephrol. 1998;12:365–70. doi: 10.1007/s004670050467.
    1. Besouw MT, Van Dyck M, Francois I, Van Hoyweghen E, Levtchenko EN. Detailed studies of growth hormone secretion in cystinosis patients. Pediatr Nephrol. 2012;27:2123–7. doi: 10.1007/s00467-012-2213-x.
    1. Greco M, Brugnara M, Zaffanello M, Taranta A, Pastore A, Emma F. Long-term outcome of nephropathic cystinosis: a 20-year single-center experience. Pediatr Nephrol. 2010;25:2459–67. doi: 10.1007/s00467-010-1641-8.
    1. Levtchenko E, Blom H, Wilmer M, van den Heuvel L, Monnens L. ACE inhibitor enalapril diminishes albuminuria in patients with cystinosis. Clin Nephrol. 2003;60:386–9. doi: 10.5414/CNP60386.
    1. Spear GS, Gubler MC, Habib R, Broyer M. Renal allografts in cystinosis and mesangial demography. Clin Nephrol. 1989;32:256–61.
    1. Kashtan CE, McEnery PT, Tejani A, Stablein DM. Renal allograft survival according to primary diagnosis: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol. 1995;9:679–84. doi: 10.1007/BF00868709.
    1. Rigden SP. Data from the ERA-EDTA registry. In: Broyer M, editor. Cystinosis. 1. Amsterdam: Elsevier; 1999. pp. 20–7.
    1. Cohen C, Charbit M, Chadefaux-Vekemans B, Giral M, Garrigue V, Kessler M, Antoine C, Snanoudj R, Niaudet P, Kreis H, Legendre C, Servais A. Excellent long-term outcome of renal transplantation in cystinosis patients. Orphanet J Rare Dis. 2015;10:90. doi: 10.1186/s13023-015-0307-9.
    1. Ehrich JH, Brodehl J, Byrd DI, Hossfeld S, Hoyer PF, Leipert KP, Offner G, Wolff G. Renal transplantation in 22 children with nephropathic cystinosis. Pediatr Nephrol. 1991;5:708–14. doi: 10.1007/BF00857880.
    1. Schneider JA, Clark KF, Greene AA, Reisch JS, Markello TC, Gahl WA, Thoene JG, Noonan PK, Berry KA. Recent advances in the treatment of cystinosis. J Inherit Metab Dis. 1995;18:387–97. doi: 10.1007/BF00710051.
    1. Markello TC, Bernardini IM, Gahl WA. Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med. 1993;328:1157–62. doi: 10.1056/NEJM199304223281604.
    1. Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med. 2007;147:242–50. doi: 10.7326/0003-4819-147-4-200708210-00006.
    1. Van Stralen KJ, Emma F, Jager KJ, Verrina E, Schaefer F, Laube GF, Lewis MA, Levtchenko EN. Improvement in the renal prognosis in nephropathic cystinosis. Clin J Am Soc Nephrol. 2011;6:2485–91. doi: 10.2215/CJN.02000311.
    1. Kleta R, Bernardini I, Ueda M, Varade WS, Phrnphutkul C, Krasnewich D, Gahl WA. Long-term follow-up of well-treated nephropathic cystinosis patients. J Pediatr. 2004;145:555–60. doi: 10.1016/j.jpeds.2004.03.056.
    1. Kimonis VE, Troendle J, Rose SR, Ynag ML, Markello TC, Gahl WA. Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis. J Clin Endocrinol Metab. 1995;80:3257–61.
    1. Van’t Hoff WG, Gretz N. The treatment of cystinosis with cysteamine and phosphocysteamine in the United Kingdom and Eire. Pediatr Nephrol. 1995;9:685–9. doi: 10.1007/BF00868711.
    1. Labbé A, Baudouin C, Deschênes G, Loirat C, Charbit M, Guest G, Niaudet P. A new gel formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis: the Cystadrops OCT-1 study. Mol Genet Metab. 2014;111:314–20. doi: 10.1016/j.ymgme.2013.12.298.
    1. Nesterova G, Williams C, Bernardini I, Gahl WA. Cystinosis: renal glomerular and renal tubular function in relation to compliance with cystine-depleting therapy. Pediatr Nephrol. 2015;30:945–51. doi: 10.1007/s00467-014-3018-x.
    1. Wenner WJ, Murphy JL. The effects of cysteamine on the upper gastrointestinal tract of children with cystinosis. Pediatr Nephrol. 1997;11:600–3. doi: 10.1007/s004670050345.
    1. Dohil R, Newbury RO, Sellers ZM, Deutsch R, Schneider JA. The evaluation and treatment of gastrointestinal disease in children with cystinosis receiving cysteamine. J Pediatr. 2003;143:224–30. doi: 10.1067/S0022-3476(03)00281-6.
    1. Dohil R, Fidler M, Barshop BA, Gangoiti J, Deutsch R, Martin M, Schneider JA. Understanding intestinal cysteamine bitartrate absorption. J Pediatr. 2006;148:764–9. doi: 10.1016/j.jpeds.2006.01.050.
    1. Dohil R, Fidler M, Barshop B, Newbury R, Sellers Z, Deutsch R, Schneider J. Esomeprazole therapy for gastric acid hypersecretion in children with cystinosis. Pediatr Nephrol. 2005;20:1786–93. doi: 10.1007/s00467-005-2027-1.
    1. Besouw M, Blom H, Tangerman A, de Graaf-Hess A, Levtchenko E. The origin of halitosis in cystinotic patients due to cysteamine treatment. Mol Genet Metab. 2007;91:228–33. doi: 10.1016/j.ymgme.2007.04.002.
    1. Ivanova E, De Leo MG, De Matteis MA, Levtchenko E. Cystinosis: clinical presentation, pathogenesis and treatment. Pediatr Endocrinol Rev. 2014;12(Suppl 1):176–84.
    1. Besouw MT, Bowker R, Dutertre JP, Emma F, Gahl WA, Greco M, Lilien MR, McKiernan J, Nobili F, Schneider JA, Skovby F, van den Heuvel LP, Hoff WG Van’t, Levtchenko EN. Cysteamine toxicity in patients with cystinosis. J Pediatr. 2011;159:1004–11.
    1. Corden BJ, Schulman JD, Schneider JA, Thoene JG. Adverse reactions to oral cysteamine use in nephropathic cystinosis. Dev Pharmacol Ther. 1981;3:25–30.
    1. Beckman DA, Mullin JJ, Assadi FK. Developmental toxicity of cysteamine in the rat: effects on embryo-fetal development. Teratology. 1998;58:96–102. doi: 10.1002/(SICI)1096-9926(199809/10)58:3/4<96::AID-TERA5>;2-7.
    1. Assadi FK, Mullin JJ, Beckman DA. Evaluation of the reproductive and developmental safety of cysteamine in the rat: effects on female reproduction and early embryonic development. Teratology. 1998;58:88–95. doi: 10.1002/(SICI)1096-9926(199809/10)58:3/4<88::AID-TERA4>;2-5.
    1. Levtchenko EN, van Dael CM, de Graaf-Hess AC, Wilmer MJ, van den Heuvel LP, Monnens LA, Blom HJ. Strict cysteamine dose regimen is required to prevent nocturnal cystine accumulation in cystinosis. Pediatr Nephrol. 2006;21:110–3. doi: 10.1007/s00467-005-2052-0.
    1. Dohil R, Fidler M, Gangoiti JA, Kaskel F, Schneider JA, Barshop BA. Twice-daily cysteamine bitartrate therapy for children with cystinosis. J Pediatr. 2010;156:71–5. doi: 10.1016/j.jpeds.2009.07.016.
    1. Levtchenko E, de Graaf-Hess A, Wilmer M, van den Heuvel L, Monnens L, Blom H. Comparison of cystine determination in mixed leukocytes vs polymorphonuclear leukocytes for diagnosis of cystinosis and monitoring of cysteamine therapy. Clin Chem. 2004;50:1686–8. doi: 10.1373/clinchem.2004.031872.
    1. Prencipe G, Caiello I, Cherqui S, Whisenant T, Petrini S, Emma F, De Benedetti F. Inflammasome activation by cystine crystals: implications for the pathogenesis of cystinosis. J Am Soc Nephrol. 2014;25:1163–9. doi: 10.1681/ASN.2013060653.
    1. Andrzejewska Z, Nevo N, Thomas L, Chhuon C, Bailleux A, Chauvet V, Courtoy PJ, Chol M, Guerrera IC, Antignac C. Cystinosin is a Component of the Vacuolar H + −ATPase-Ragulator-Rag Complex Controlling Mammalian Target of Rapamycin Complex 1 Signaling. J Am Soc Nephrol. 2015 [Epub ahead of print].
    1. Ivanova EA, De Leo MG, Van Den Heuvel L, Pastore A, Dijkman H, De Matteis MA, Levtchenko EN. Endo-lysosomal dysfunction in human proximal tubular epithelial cells deficient for lysosomal cystine transporter cystinosin. PLoS One. 2015;10 doi: 10.1371/journal.pone.0120998.
    1. 123- Ivanova EA, van den Heuvel LP, Elmonem MA, De Smedt H, Missiaen L, Pastore A, Mekahli D, Bultynck G, Levtchenko E. Altered mTOR signalling in nephropathic cystinosis. J Inherit Metab Dis. 2016 [In press].
    1. Jansen J, Schophuizen CMS, Wilmer MJ, Lahham SH, Mutsaers HA, Wetzels JF, Bank RA, van den Heuvel LP, Hoenderop JG, Masereeuw R. A morphological and functional comparison of proximal tubule cell lines established from human urine and kidney tissue. Exp Cell Res. 2014;323:87–99. doi: 10.1016/j.yexcr.2014.02.011.
    1. Oliveira Arcolino F, Tort Piella A, Papadimitriou E, Bussolati B, Antonie DJ, Murray P, van den Heuvel L, Levtchenko E. Human Urine as a Noninvasive Source of Kidney Cells. Stem Cells Int. 2015;2015:362562. doi: 10.1155/2015/362562.
    1. Cherqui S, Kalatzis V, Forestier L, Poras I, Antignac C. Identification and characterisation of the murine homologue of the gene responsible for cystinosis. Ctns BMC Genomics. 2000;1:2. doi: 10.1186/1471-2164-1-2.
    1. Nevo N, Chol M, Bailleux A, Kalatzis V, Morisset L, Devuyst O, Gubler MC, Antignac C. Renal phenotype of the cystinosis mouse model is dependent upon genetic background. Nephrol Dial Transplant. 2010;25:1059–66. doi: 10.1093/ndt/gfp553.
    1. Kerfoot SA, Jung S, Golob K, Torgerson TR, Hahn SH. Tryptic peptide screening for primary immunodeficiency disease by LC/MS-MS. Proteomics Clin Appl. 2012;6:394–402. doi: 10.1002/prca.201100096.
    1. Sansanwal P, Sarwal MM. Abnormal mitochondrial autophagy in nephropathic cystinosis. Autophagy. 2010;6:971–3. doi: 10.4161/auto.6.7.13099.
    1. Galarreta CI, Forbes MS, Thornhill BA, Antignac C, Gubler MC, Nevo N, Murphy MP, Chevalier RL. The swan-neck lesion: proximal tubular adaptation to oxidative stress in nephropathic cystinosis. Am J Physiol Renal Physiol. 2015;308:F1155–66. doi: 10.1152/ajprenal.00591.2014.
    1. Syres K, Harrison F, Tadlock M, Jester JV, Simpson J, Roy S, Salomon DR, Cherqui S. Successful treatment of the murine model of cystinosis using bone marrow cell transplantation. Blood. 2009;114:2542–52. doi: 10.1182/blood-2009-03-213934.
    1. Harrison F, Yeagy BA, Rocca CJ, Kohn DB, Salomon DR, Cherqui S. Hematopoietic stem cell gene therapy for the multisystemic lysosomal storage disorder cystinosis. Mol Ther. 2013;21:433–44. doi: 10.1038/mt.2012.214.

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