Cystinosis and Its Renal Complications in Children

Reference work entry

Abstract

Nephropathic cystinosis [1–3] deserves a special place in the annals of clinical medicine as the first treatable lysosomal storage disease. The pathophysiology itself, based upon the formation of cystine crystals within the lysosomes of cells, is remarkable. The presence of cystine crystals provides a clue to the basic defect in cystinosis, i.e., failure to transport cystine out of lysosomes [4–6]. This created a new area of biomedical investigation, explained the lysosome’s function in salvaging small molecules for reutilization by the cell, and revealed a new category of lysosomal storage disorders due to transport defects rather than enzyme deficiencies [7]. Even more striking, a rational therapy of cystine depletion (i.e., cysteamine) emerged [8–10], transforming nephropathic cystinosis from a universally fatal disease to a treatable chronic disorder with a decent quality of life and increased life span. Today, physicians can even observe the gradual dissolution of cystine crystals by cysteamine eyedrops bathing the corneas of patients’ eyes [11–13].

Keywords

Osteoporosis Influenza Cysteine Retina Testosterone 

References

  1. 1.
    Nesterova G, Gahl W. Cystinosis. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, Seattle: University of Washington; 2013. 1997–2013. www.genetests.org
  2. 2.
    Gahl WA, Thoene JG, Schneider JA. Cystinosis: a disorder of lysosomal membrane transport. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, Vogelstein B, editors. The metabolic and molecular bases of inherited disease, vol. 4. 8th ed. New York: McGraw-Hill; 2001. p. 5085–108.Google Scholar
  3. 3.
    Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347:111–21.PubMedCrossRefGoogle Scholar
  4. 4.
    Gahl WA, Bashan N, Tietze F, et al. Cystine transport is defective in isolated leukocyte lysosomes from patients with cystinosis. Science. 1982;217:1263–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Gahl WA, Tietze F, Bashan N, et al. Defective cystine exodus from isolated lysosome-rich fractions of cystinotic leucocytes. J Biol Chem. 1982;257:9570–5.PubMedGoogle Scholar
  6. 6.
    Jonas AJ, Smith ML, Schneider JA. ATP-dependent lysosomal cystine efflux is defective in cystinosis. J Biol Chem. 1982;257:13185–8.PubMedGoogle Scholar
  7. 7.
    Gahl WA, Thoene JG. Cystinosis: a disorder of lysosomal membrane transport, chapter 199. In: The metabolic and molecular bases of inherited disease. In press to be published online, 2013.Google Scholar
  8. 8.
    Thoene JG, Oshima RG, Crawhall JC, et al. Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo. J Clin Invest. 1976;58:180–9.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Gahl WA, Reed GF, Thoene JG, et al. Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med. 1987;316:971–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Markello TC, Bernardini IM, Gahl WA. Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med. 1993;328:1157–62.PubMedCrossRefGoogle Scholar
  11. 11.
    Kaiser-Kupfer MI, Fujikawa L, Kuwabara T, Gahl WA. Removal of corneal crystals by topical cysteamine in nephropathic cystinosis. N Engl J Med. 1987;316:775–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Kaiser-Kupfer MI, Gazzo MA, Datiles MB, et al. A randomized placebo-controlled trial of cysteamine eyedrops in nephropathic cystinosis. Arch Ophthalmol. 1990;108:689–93.PubMedCrossRefGoogle Scholar
  13. 13.
    Gahl WA, Kuehl EM, Iwata F, et al. Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eyedrops. Mol Genet Metab. 2000;71:100–21.PubMedCrossRefGoogle Scholar
  14. 14.
    Abderhalden E. Familiare cystindiathese. Z Physiol Chem. 1903;38:557–61.CrossRefGoogle Scholar
  15. 15.
    Dent CE. The amino-aciduria in Fanconi syndrome. A study making extensive use of techniques based on paper partition chromatography. Biochem J. 1947;41:240–53.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Schulman JD, Bradley KH, Seegmiller JE. Cystine: compartmentalization within lysosomes in cystinotic leukocytes. Science. 1969;166:1152–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Theodoropoulos DS, Krasnewich D, Kaiser-Kupfer MI, Gahl WA. Classical nephropathic cystinosis as an adult disease. JAMA. 1993;270:2200–4.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    Segal S, Their SO. Cystinuria. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, et al., editors. The metabolic basis of inherited disease. 5th ed. New York: McGraw-Hill; 1983. p. 1774–91.Google Scholar
  20. 20.
    Patrick AD, Lake BD. Cystinosis: electron microscopic evidence of lysosomal storage of cystine in lymph node. J Clin Pathol. 1968;21:571–5.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Tietze F, Bradley KH, Schulman JD. Enzymatic reduction of cystine by subcellular fractions of cultured and peripheral leukocytes form normal and cystinotic individuals. Pediatr Res. 1972;6:649–58.PubMedCrossRefGoogle Scholar
  22. 22.
    Steinherz R, Tietze F, Gahl WA, et al. Cystine accumulation and clearance by normal and cystinotic leukocytes exposed to cystine dimethylester. Proc Natl Acad Sci U S A. 1982;79:4446–50.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Gahl WA, Tietze F, Bashan N, et al. Characteristics of cystine counter-transport in normal and cystinotic lysosome-rich leucocyte granular fraction. Biochem J. 1983;216:393–400.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Gahl WA, Bashan N, Tietze F, Schulman JD. Lysosomal cystine counter-transport in the detection of heterozygotes for cystinosis. Am J Hum Genet. 1984;36:277–82.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Town M, Jean G, Cherqui S, et al. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet. 1998;18:319–24.PubMedCrossRefGoogle Scholar
  26. 26.
    Kalatzis V, Cherqui S, Antignac C, Gasnier B. Cystinosis, the protein defective in cystinosis, is a H+-driven lysosomal cystine transporter. EMBO J. 2001;20:5940–9.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Mahoney CP, Striker GE. Early development of the renal lesions in infantile cystinosis. Pediatr Nephrol. 2000;15:50–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Chevalier RL, Forbes MS. Generation and evolution of atubular glomeruli in the progression of renal disorders. Nephrol Dial Transplant. 2009;24(7):2161–9.CrossRefGoogle Scholar
  29. 29.
    Larsen CP, Walker PD, Thoene JG. The incidence of atubular glomeruli in nephropathic cystinosis renal biopsies. Mol Genet Metab. 2010;101(4):417–20.PubMedCrossRefGoogle Scholar
  30. 30.
    Wong VG, Leitman PS, Seegmiller JE. Alterations of pigment epithelium in cystinosis. Arch Ophthalmol. 1967;77:361–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Kaiser-Kupfer MI, Caruso RC, Minckler DS, Gahl WA. Long-term ocular manifestations in nephropathic cystinosis post-renal transplantation. Arch Ophthalmol. 1986;104:706–11.PubMedCrossRefGoogle Scholar
  32. 32.
    Gahl WA, Dalakas M, Charnas L, et al. Myopathy and cystine storage in muscles in a patient with nephropathic cystinosis. N Engl J Med. 1988;319:1461–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Charnas L, Luciano C, Dalakas M, et al. Distal vacuolar myopathy in nephropathic cystinosis. Ann Neurol. 1994;35:181–8.PubMedCrossRefGoogle Scholar
  34. 34.
    O’Brien K, Hussain N, Warady B, et al. Nodular regenerative hyperplasia and severe portal hypertension in cystinosis. Clin Gastroenterol Hepatol. 2006;4:387–94.PubMedCrossRefGoogle Scholar
  35. 35.
    Sansanwal P, Yen B, Ying L, Gahl WA, Sarwal M. Mitochondrial autophagy in cystinosis may determine the phenotype of renal injury. J Am Soc Nephrol. 2010;21:272–83.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Park M, Helip-Wooley A, Thoene J. Lysosomal cystine storage augments apoptosis in cultured human fibroblasts and renal tubular epithelial cells. J Am Soc Nephrol. 2002;13:2878–87.PubMedCrossRefGoogle Scholar
  37. 37.
    Raggi C, Luciani A, Nevo N, Antignac C, Terryn S, Devuyst O. Dedifferentiation and aberrations of the endolysosomal compartment characterize the early stage of nephropathic cystinosis. Hum Mol Genet. 2014;23(9):2266–78.PubMedCrossRefGoogle Scholar
  38. 38.
    Bellomo F, Corallini S, Pastore A, Palma A, Laurenzi C, Emma F, Taranta A. Modulation of CTNS gene expression by intracellular thiols. Free Radic Biol Med. 2010;48(7):865–72.PubMedCrossRefGoogle Scholar
  39. 39.
    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(6):1163–9.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Bois E, Feingold J, Frenay P, Briard ML. Infantile cystinosis in France: genetics, incidence, geographic distribution. J Med Genet. 1976;13:434–8.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    McDowell GA, Gahl WA, Stephenson L, et al. Linkage of the gene for cystinosis to markers on the short arm of chromosome 17. Nat Genet. 1995;10:246–8.CrossRefGoogle Scholar
  42. 42.
    Shotelersuk V, Larson D, Anikster Y, et al. CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet. 1998;63:1352–62.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Attard M, Jean G, Forestier L, et al. Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin. Hum Mol Genet. 1999;8:2507–14.PubMedCrossRefGoogle Scholar
  44. 44.
    Phornphutkul C, Anikster Y, Huizing M, et al. The promoter of a lysosomal membrane transporter gene, CTNS, binds Sp-1, shares sequences with the promoter of an adjacent gene (CARKL), and causes cystinosis if mutated in a critical region. Am J Hum Genet. 2001;69:712–21.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Touchman JW, Anikster Y, Dietrich NL, et al. The genomic region encompassing the nephropathic cystinosis gene (CTNS): complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion. Genome Res. 2000;10:165–73.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Anikster Y, Lucero C, Touchman JW, et al. Identification and detection of the common 65-kb deletion breakpoint in the nephropathic cystinosis gene (CTNS). Mol Genet Metab. 1999;66:111–6.PubMedCrossRefGoogle Scholar
  47. 47.
    McGowan-Jordan J, Stoddard K, Podolsky L, et al. Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation. Eur J Hum Genet. 1999;7:671–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Rupar CA, Matsell D, Surry S, Siu V. A G339R mutation in the CTNS gene is a common cause of nephropathic cystinosis in the south western Ontario Amish Mennonite population. J Med Genet. 2001;38:615–6.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Thoene J, Lemons R, Anikster Y, et al. Mutations of CTNS causing intermediate cystinosis. Mol Genet Metab. 1999;67:283–93.PubMedCrossRefGoogle Scholar
  50. 50.
    Gahl WA, Tietze F. Lysosomal cystine transport in cystinosis variants and their parents. Pediatr Res. 1987;21:193–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Anikster Y, Lucero C, Guo J, et al. Ocular, non-nephropathic cystinosis: clinical, biochemical and molecular correlations. Pediatr Res. 2000;47:17–23.PubMedCrossRefGoogle Scholar
  52. 52.
    Cherqui CS, Sevin C, Kalatzis V, et al. Generation and characterization of a cystinosis murine model. J Am Soc Nephrol. 2001;12:A2856.Google Scholar
  53. 53.
    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(4):1059–66.PubMedCrossRefGoogle Scholar
  54. 54.
    Nesterova G, Gahl WA. Cystinosis. In: Kelly CR, Landman J, editors. The Netter collection of medical illustrations: urinary system. London: Elsevier; 2012. p. 159–60.Google Scholar
  55. 55.
    Drube J, Schiffer E, Mischak H, Kemper MJ, Neuhaus T, Pape L, Lichtinghagen R, Ehrich JH. Urinary proteome pattern in children with renal Fanconi syndrome. Nephrol Dial Transplant. 2009;24(7):2161–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Gahl WA. Cystinosis coming of age. Adv Pediatr. 1986;33:95–126.PubMedGoogle Scholar
  57. 57.
    Theodoropoulos DS, Shawker TH, Heinrichs C, Gahl WA. Medullary nephrocalcinosis in nephropathic cystinosis. Pediatr Nephrol. 1995;9:412–8.PubMedCrossRefGoogle Scholar
  58. 58.
    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(6):1256–69.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Gahl WA, Bernardini I, Dalakas M, et al. Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome. J Clin Invest. 1988;81:549–60.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Charnas LR, Bernardini I, Rader D, et al. Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. N Engl J Med. 1991;324:1318–25.PubMedCrossRefGoogle Scholar
  61. 61.
    Middleton R, Bradbury M, Webb N, et al. Cystinosis. A clinicopathological conference. “From toddlers to twenties and beyond” Adult-Paediatric Nephrology Interface Meeting, Mancheste 2001. Nephrol Dial Transplant. 2003;18:2492–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Gretz N, Manz F, Augustin R, et al. Survival time in cystinosis. A collaborative study. Proc Eur Dial Transplant Assoc. 1983;19:582–9.PubMedGoogle Scholar
  63. 63.
    Lucky AW, Howley PM, Megyesi K, et al. Endocrine studies in cystinosis: compensated primary hypothyroidism. J Pediatr. 1977;91:204–10.PubMedCrossRefGoogle Scholar
  64. 64.
    Wuhl E, Haffner D, Gretz N, et al. Treatment with recombinant human growth hormone in short children with nephropathic cystinosis: no evidence for increased deterioration rate of renal function. Pediatr Res. 1998;43:484–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Gahl WA, Schneider JA, Thoene JG, Chesney R. The course of nephropathic cystinosis after age 10 years. J Pediatr. 1986;109:605–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Kimonis VE, Troendle J, Yang ML, et al. Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis. J Clin Endocrinol Metab. 1995;80:3257–61.PubMedGoogle Scholar
  67. 67.
    Bercu BB, Orloff S, Schulman JD. Partial pituitary resistance to thyroid hormone in cystinosis. J Clin Endocrinol Metab. 1980;51:1262–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Spilkin AM, Ballantyne AO, Babchuck LR, Trauner DA. Non-verbal deficits in young children with a genetic metabolic disorder: WPPSI-III performance in cystinosis. Am J Med Genet B Neuropsychiatr Genet. 2007;144:444–7.CrossRefGoogle Scholar
  69. 69.
    Wolff G, Ehrich JH, Offner G, Brodehl J. Psychosocial and intellectual development in 12 patients with infantile nephropathic cystinosis. Acta Paediatr Scand. 1982;71:1007–11.PubMedCrossRefGoogle Scholar
  70. 70.
    Ballantyne AO, Trauner DA. Neurobehavioral consequences of a genetic metabolic disorder: visual processing deficits in infantile nephropathic cystinosis. Neuropsychiatry Neuropsychol Behav Neurol. 2000;13:254–63.PubMedGoogle Scholar
  71. 71.
    Colah S, Trauner DA. Tactile recognition in infantile nephropathic cystinosis. Dev Med Child Neurol. 1997;39:409–13.PubMedCrossRefGoogle Scholar
  72. 72.
    Nichols SL, Press GA, Schneider JA, Trauner DA. Cortical atrophy and cognitive performance in infantile nephropathic cystinosis. Pediatr Neurol. 1990;6:379–81.PubMedCrossRefGoogle Scholar
  73. 73.
    Delgado G, Schatz A, Nichols S, et al. Behavioral profiles of children with infantile nephropathic cystinosis. Dev Med Child Neurol. 2005;47:403–7.PubMedCrossRefGoogle Scholar
  74. 74.
    Avner ED, Ellis D, Jaffe R. Veno-occlusive disease of the liver associated with cysteamine treatment of nephropathic cystinosis. J Pediatr. 1983;102:793–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Gahl WA, Hubbard VS, Orloff S. Decreased sweat production in cystinosis. J Pediatr. 1984;104:904–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Dogulu CF, Tsilou E, Rubin B, et al. Idiopathic intracranial hypertension in cystinosis. J Pediatr. 2004;145:673–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Schneider JA, Bradley K, Seegmiller JE. Increased cystine in leukocytes from individuals homozygous and heterozygous for cystinosis. Science. 1967;157:1321–2.PubMedCrossRefGoogle Scholar
  78. 78.
    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.PubMedGoogle Scholar
  79. 79.
    Nesterova G, Gahl W. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol. 2008;23(6):863–78.PubMedCrossRefGoogle Scholar
  80. 80.
    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(3):339–42.PubMedCrossRefGoogle Scholar
  81. 81.
    Smith ML, Pellet OL, Cass MM, et al. Prenatal diagnosis of cystinosis utilizing chorionic villus sampling. Prenat Diagn. 1987;7:23–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Schneider JA, Verroust FM, Kroll WA, et al. Prenatal diagnosis of cystinosis. N Engl J Med. 1974;290:878–82.PubMedCrossRefGoogle Scholar
  83. 83.
    Smith ML, Clark KF, Davis SE, et al. Diagnosis of cystinosis with use of placenta. N Engl J Med. 1989;321:397–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Palacin M, Goodyer P, Nunes V, Gasparini P. Cystinuria. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, Vogelstein B, editors. The metabolic and molecular bases of inherited disease, vol. 4. 8th ed. New York: McGraw-Hill; 2001. p. 4909–32.Google Scholar
  85. 85.
    Pisoni RL, Thoene JG, Christensen HN. Detection and characterization of carrier-mediated cationic amino acid transport in lysosomes of normal and cystinotic human fibroblasts. J Biol Chem. 1985;260:4791–8.PubMedGoogle Scholar
  86. 86.
    Schneider JA, Schlesselman JJ, Mendoza SA, et al. Ineffectiveness of ascorbic acid therapy in nephropathic cystinosis. N Engl J Med. 1979;300:756–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Gahl WA, Schneider JA, Aula PP. Lysosomal transport disorders: cystinosis and sialic acid storage disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, editors. The metabolic and molecular bases of inherited disease, vol. 3. 7th ed. New York: McGraw-Hill; 1995. p. 3763–97.Google Scholar
  88. 88.
    Gahl WA, Ingelfinger J, Mohan P, et al. Intravenous cysteamine therapy for nephropathic cystinosis. Pediatr Res. 1995;38:579–84.PubMedCrossRefGoogle Scholar
  89. 89.
    Kleta R, Bernardini I, Ueda M, et al. Long-term follow-up of well-treated nephropathic cystinosis patients. J Pediatr. 2004;145:555–60.PubMedCrossRefGoogle Scholar
  90. 90.
    Corden BJ, Schulman JD, Schneider JA, Thoene JG. Adverse reactions to oral cysteamine use in nephropathic cystinosis. Dev Pharmacol Ther. 1981;3:25–30.PubMedGoogle Scholar
  91. 91.
    Besouw MTP, Bowker R, Dutertre J-P, Emma F, Gahl WA, Greco M, Lilien MR, McKiernan J, Nobili F, Schneider JA, Skovby F, van den Heuvel LP, Van’t Hoff WG, Levtchenko EN. Cysteamine toxicity in patients with cystinosis. J Pediatr. 2011;159:1004–11. doi:10.1016/j.jpeds.2011.05.057.PubMedCrossRefGoogle Scholar
  92. 92.
    Besouw MT, Schneider J, Janssen MC, Greco M, Emma F, Cornelissen EA, Desmet K, Skovby F, Nobili F, Lilien MR, De Paepe A, Malfait F, Symoens S, van den Heuvel LP, Levtchenko EN. Copper deficiency in patients with cystinosis with cysteamine toxicity. J Pediatr. 2013;163(3):754–60.PubMedCrossRefGoogle Scholar
  93. 93.
    Smolin LA, Clark KF, Thoene JG, et al. A comparison of the effectiveness of cysteamine and phosphocysteamine in elevating plasma cysteamine concentration and decreasing leukocyte free cystine in nephropathic cystinosis. Pediatr Res. 1988;23:616–20.PubMedCrossRefGoogle Scholar
  94. 94.
    Gahl WA, Gregg RE, Hoeg JM, Fisher EA. Cysteamine alteration of apolipoprotein E isoelectric focusing patterns in vivo. Am J Med Genet. 1985;20:409–17.PubMedCrossRefGoogle Scholar
  95. 95.
    Fidler MC, Barshop BA, Gangoiti JA, et al. Pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion. Br J Clin Pharmacol. 2007;63:36–40.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Gahl WA, Charnas L, Markello TC, et al. Parenchymal organ cystine depletion with long term cysteamine therapy. Biochem Med Metab Biol. 1992;48:275–85.PubMedCrossRefGoogle Scholar
  97. 97.
    Huynh N, Gahl WA, Bishop RJ. Cysteamine ophthalmic solution 0.44 % for the treatment of corneal cystine crystals in cystinosis. Expert Rev Ophthalmol. 2013;8:341–5.CrossRefGoogle Scholar
  98. 98.
    Tsilou ET, Thompson D, Lindblad AS, et al. A multicenter randomised double-masked clinical trial of a new formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis. Br J Ophthalmol. 2003;87:28–31.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    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(2):433–44. doi:10.1038/mt.2012.214.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Müller-Felber W, Schröder M, Hirschmann M, et al. Neurophysiological testing in long-standing cystinosis. Electromyogr Clin Neurophysiol. 1999;39:67–70.PubMedGoogle Scholar
  101. 101.
    Sonies B, Ekman EF, Andersson H, et al. Swallowing dysfunction in nephropathic cystinosis. N Engl J Med. 1990;323:565–70.PubMedCrossRefGoogle Scholar
  102. 102.
    Anikster Y, Lacbawan F, Brantly M, et al. Pulmonary dysfunction in adults with nephropathic cystinosis. Chest. 2001;119:394–401.PubMedCrossRefGoogle Scholar
  103. 103.
    Fivush B, Green OC, Porter CC, et al. Pancreatic endocrine insufficiency in post-transplant cystinosis. Am J Dis Child. 1987;141:1087–9.PubMedGoogle Scholar
  104. 104.
    Fivush B, Flick JA, Gahl WA. Pancreatic exocrine insufficiency in a patient with nephropathic cystinosis. J Pediatr. 1988;112:49–51.PubMedCrossRefGoogle Scholar
  105. 105.
    Chik CL, Friedman A, Merriam GR, Gahl WA. Pituitary-testicular function in nephropathic cystinosis. Ann Intern Med. 1993;119:568–75.PubMedCrossRefGoogle Scholar
  106. 106.
    Reiss RE, Kuwabara T, Smith ML, Gahl WA. Successful pregnancy despite placental cystine crystals in a woman with nephropathic cystinosis. N Engl J Med. 1988;319:223–6.PubMedCrossRefGoogle Scholar
  107. 107.
    Fink JK, Brouwers P, Barton N, et al. Neurologic complications in longstanding nephropathic cystinosis. Arch Neurol. 1989;46:543–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Jonas AJ, Conley SB, Marshall R, et al. Nephropathic cystinosis with central nervous system involvement. Am J Med. 1987;83:966–70.PubMedCrossRefGoogle Scholar
  109. 109.
    Cochat P, Drachman R, Gagnadoux MF, et al. Cerebral atrophy and nephropathic cystinosis. Arch Dis Child. 1986;61:401–3.PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Tsilou ET, Rubin B, Reed G, et al. Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy. Ophthalmology. 2006;113:1002–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Ueda M, O’Brien K, Rosing DR, et al. Coronary artery and other vascular calcifications in cystinosis patients after kidney transplantation. Clin J Am Soc Nephrol. 2006;1:555–62.PubMedCrossRefGoogle Scholar
  112. 112.
    Zimakas PJ, Sharma AK, Rodd CJ. Osteopenia and fractures in cystinotic children post renal transplantation. Pediatr Nephrol. 2003;18(4):384–90.PubMedGoogle Scholar
  113. 113.
    Sonies BC, Almajid P, Kleta R, et al. Swallowing dysfunction in 101 patients with nephropathic cystinosis: benefit of long-term cysteamine therapy. Medicine. 2005;84:137–46.PubMedCrossRefGoogle Scholar
  114. 114.
    Aula P, Gahl WA. Sialic acid storage diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, Vogelstein B, editors. The metabolic and molecular bases of inherited disease, vol. 4. 8th ed. New York: McGraw-Hill; 2001. p. 5109–20.Google Scholar
  115. 115.
    Fenton WA, Gravel RA, Rosenblatt DS. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, Vogelstein B, editors. The metabolic and molecular bases of inherited disease, vol. 2. 8th ed. New York: McGraw-Hill; 2001. p. 2165–93.Google Scholar
  116. 116.
    Nesterova G, Gahl WA. Infantile nephropathic cystinosis standards of care – a reference for people with infantile nephropathic cystinosis, their families, and medical team. Cystinosis Research Network. https://cystinosis.org/images/family-support/resources/CRN_Standards_12pgloRes.pdf (2012).

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2016

Authors and Affiliations

  1. 1.Section on Human Biochemical Genetics, Medical Genetics BranchNational Human Genome Research Institute, National Institutes of HealthBethesdaUSA

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