Cystinose

Zusammenfassung

Die Cystinose ist eine sehr seltene autosomal-rezessive Speichererkrankung, die mit einer Inzidenz von 1 : 150 000 – 1 : 200 000 auftritt. Ursächlich sind Mutationen im CTNS-Gen, welches das lysosomale Membranprotein Cystinosin codiert, das für den Transport von Cystin aus dem Lysosom in das Zytoplasma verantwortlich ist. In der Folge kommt es zur Akkumulation von Cystin in fast allen Zellen und Geweben, insbesondere den Nieren, wodurch sich die Multiorganbeteiligung erklärt. Der Verlauf und die Prognose konnte durch Einführung der medikamentösen Therapie mit Cysteamin Mitte der 1980er-Jahre und der Möglichkeit der Nierenersatztherapie im Kindesalter entscheidend verbessert werden. Während die Patienten früher ohne Therapie in einer terminalen Niereninsuffizienz während des 1. Lebensjahrzehnts verstorben sind, erreicht heute die Mehrzahl der Patienten das Erwachsenenalter ohne eine Nierenersatztherapie. Die ältesten Patienten sind heute ca. 40 Jahre alt. Für die Morbidität und die Mortalität spielt neben dem Zeitpunkt des Therapiebeginns auch die lebenslang notwendige adäquate Cysteamin-Therapie eine entscheidende Rolle. Die Seltenheit der Erkrankung und die Multiorganbeteiligung stellt für die Betroffenen und die Versorger dieser Patientengruppe eine enorme Herausforderung dar.

Schlüsselwörter

Cystinose - Diagnose - Therapie - Verlauf - Prognose

• References/Literatur

• 1 Abderhalden E. Familiäre Cystindiathese. Z Biol Chem 1903; 38: 557-561
• 2 Lignac GOE. Über Störung des Cystinstoffwechsels bei Kindern. Dtsch Arch Klin Med 1924; 145: 139-150
• 3 Fanconi G. Die nicht diabetischen Glykosurien und Hyperglykaemien des aelteren Kindes. Jb Kinderheilkd 1931; 133: 257-300
• 4 Haffner D, Weinfurth A, Manz F. et al. Long-term outcome of paediatric patients with hereditary tubular disorders. Nephron 1999; 83: 250-260
• 5 Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med 2002; 347: 111-121
• 6 Gahl WA, Bashan N, Tietze F. et al. Cystine transport is defective in isolated leukocyte lysosomes from patients with cystinosis. Science 1982; 217: 1263-1265
• 7 Nesterova G, Gahl WA. Cystinosis: the evolution of a treatable disease. Pediatr Nephrol 2013; 28: 51-59
• 8 Nesterova G, Gahl W. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol 2008; 23: 863-878
• 9 Kaiser-Kupfer MI, Caruso RC, Minkler DS. et al. Long-term ocular manifestations in nephropathic cystinosis. Arch Ophthalmol 1986; 104: 706-711
• 10 Gahl WA, Reed GF, Thoene JG. et al. Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med 1987; 316: 971-977
• 11 Theodoropoulos DS, Krasnewich D, Kaiser-Kupfer MI. et al. Classic nephropathic cystinosis as an adult disease. JAMA 1993; 270: 2200-2204
• 12 Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med 2007; 147: 242-250
• 13 Servais A, Morinière V, Grünfeld JP. et al. Late-onset nephropathic cystinosis: clinical presentation, outcome, and genotyping. Clin J Am Soc Nephrol 2008; 3: 27-35
• 14 Anikster Y, Lucero C, Guo J. et al. Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations. Pediatr Res 2000; 47: 17-23
• 15 Elmonem MA, Veys KR, Soliman NA. et al. Cystinosis: a review. Orphanet J Rare Dis 2016; 11: 47
• 16 David D, Princiero Berlingerio S, Elmonem MA. et al. Molecular Basis of Cystinosis: Geographic Distribution, Functional Consequences of Mutations in the CTNS Gene, and Potential for Repair. Nephron 2019; 141: 133-146
• 17 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: 319-324
• 18 Levtchenko E, van den Heuvel L, Emma F. et al. Clinical utility gene card for: cystinosis. Eur J Hum Genet 2014;
• 19 Kiehntopf M, Schickel J, von der Gönne B. et al. Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis. Hum Mutat 2002; 20: 237
• 20 Shotelersuk V, Larson D, Anikster Y. et al. CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet 1998; 63: 1352-1362
• 21 Soliman NA, Elmonem MA, van den Heuvel L. et al. Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis. JIMD Rep 2014; 14: 87-97
• 22 Hutchesson AC, Bundey S, Preece MA. et al. 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: 366-370
• 23 Hohenfellner K, Bergmann C, Fleige T. et al. Molecular based newborn screening in Germany: Follow-up for cystinosis. Mol Genet Metab Rep 2019; 21: 100514
• 24 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: 2878-2887
• 25 Levtchenko EN, Wilmer MJG, Janssen AJM. et al. Decreased intracellular ATP content and intact mitochondrial energy generating capacity in human cystinotic fibroblasts. Pediatr Res 2006; 59: 287-292
• 26 Wilmer MJ, Emma F, Levtchenko EN. The pathogenesis of cystinosis: mechanisms beyond cystine accumulation. Am J Physiol Renal Physiol 2010; 299: F905-916
• 27 Napolitano G, Johnson JL, He J. et al. Impairment of chaperone-mediated autophagy leads to selective lysosomal degradation defects in the lysosomal storage disease cystinosis. EMBO Mol Med 2015; 7: 158-174
• 28 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: 100-120
• 29 Manz F, Gretz N. Progression of chronic renal failure in a historical group of patients with nephropathic cystinosis. European Collaborative Study on Cystinosis. Pediatr Nephrol 1994; 8: 466-471
• 30 Thoene JG, Oshima RG, Crawhall JC. et al. Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo. J Clin Invest 1976; 58: 180-189
• 31 Jézégou A, Llinares E, Anne C. et al. 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-E3443
• 32 Markello TC, Bernardini IM, Gahl WA. Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med 1993; 328: 1157-1162
• 33 Gahl WA, Charnas L, Markello TC. et al. Parenchymal organ cystine depletion with long-term cysteamine therapy. Biochem Med Metab Biol 1992; 48: 275-285
• 34 Nesterova G, Gahl WA. Cystinosis. 2001 Mar 22, last revision: 2017 Dec 7. In: GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle. 1993–2023; Accessed February 20, 2023 at: https://www.ncbi.nlm.nih.gov/books/NBK1400/
• 35 Bouazza N, Tréluyer JM, Ottolenghi C. et al. Population pharmacokinetics and pharmacodynamics of cysteamine in nephropathic cystinosis patients. Orphanet J Rare Dis 2011; 6: 86
• 36 Belldina EB, Huang MY, Schneider JA. et al. Steady-state pharmacokinetics and pharmacodynamics of cysteamine bitartrate in paediatric nephropathic cystinosis patients. Br J Clin Pharmacol 2003; 56: 520-525
• 37 Besouw M, Blom H, Tangerman A. et al. The origin of halitosis in cystinotic patients due to cysteamine treatment. Mol Genet Metab 2007; 91: 228-233
• 38 Ariceta G, Lara E, Camacho JA. et al. Cysteamine (Cystagon^®) adherence in patients with cystinosis in Spain: successful in children and a challenge in adolescents and adults. Nephrol Dial Transplant 2015; 30: 475-480
• 39 Dohil R, Newbury RO, Sellers ZM. et al. The evaluation and treatment of gastrointestinal disease in children with cystinosis receiving cysteamine. J Pediatr 2003; 143: 224-230
• 40 Besouw MTP, Bowker R, Dutertre JP. et al. Cysteamine toxicity in patients with cystinosis. J Pediatr 2011; 159: 1004-1011
• 41 Elenberg E, Norling LL, Kleinman RE. et al. Feeding problems in cystinosis. Pediatr Nephrol 1998; 12: 365-370
• 42 Mahoney CP, Striker GE. Early development of the renal lesions in infantile cystinosis. Pediatr Nephrol 2000; 15: 50-56
• 43 Kleta R, Bernardini I, Ueda M. et al. Long-term follow-up of well-treated nephropathic cystinosis patients. J Pediatr 2004; 145: 555-560
• 44 Emma F, Hoff WV, Hohenfellner K. et al. An international cohort study spanning five decades assessed outcomes of nephropathic cystinosis. Kidney Int 2021; 100: 1112-1123
• 45 Hohenfellner K, Nießl C, Haffner D. et al. Beneficial effects of starting oral cysteamine treatment in the first 2 months of life on glomerular and tubular kidney function in infantile nephropathic cystinosis. Mol Genet Metab 2022; 136: 282-288
• 46 Fleige T, Burggraf S, Czibere L. et al. Next generation sequencing as second-tier test in high-throughput newborn screening for nephropathic cystinosis. Eur J Hum Genet 2020; 28: 193-201
• 47 Nießl C, Boulesteix AL, Oh J. et al. Relationship between age at initiation of cysteamine treatment, adherence with therapy, and glomerular kidney function in infantile nephropathic cystinosis. Mol Genet Metab 2022; 136: 268-273
• 48 Spicer RA, Clayton PA, McTaggart SJ. et al. Patient and graft survival following kidney transplantation in recipients with cystinosis: a cohort study. Am J Kidney Dis 2015; 65: 172-173
• 49 Gahl WA, Dalakas MC, Charnas L. et al. Myopathy and cystine storage in muscles in a patient with nephropathic cystinosis. N Engl J Med 1988; 319: 1461-1464
• 50 Sonies BC, Almajid P, Kleta R. et al. Swallowing dysfunction in 101 patients with nephropathic cystinosis: benefit of long-term cysteamine therapy. Medicine (Baltimore) 2005; 84: 137-146
• 51 Dogulu CF, Tsilou E, Rubin B. et al. Idiopathic intracranial hypertension in cystinosis. J Pediatr 2004; 145: 673-678
• 52 Fink JK, Brouwers P, Barton N. et al. Neurologic complications in long-standing nephropathic cystinosis. Arch Neurol 1989; 46: 543-548
• 53 Hohenfellner K, Rauch F, Ariceta G. et al. Management of bone disease in cystinosis: Statement from an international conference. J Inherit Metab Dis 2019; 42: 1019-1029
• 54 Florenzano P, Ferreira C, Nesterova G. et al. Skeletal Consequences of Nephropathic Cystinosis. J Bone Miner Res 2018; 33: 1870-1880
• 55 Wühl E, Haffner D, Offner G. et al. Long-term treatment with growth hormone in short children with nephropathic cystinosis. J Pediatr 2001; 138: 880-887
• 56 Beckman DA, Mullin JJ, Assadi FK. Developmental toxicity of cysteamine in the rat: effects on embryo-fetal development. Teratology 1998; 58: 96-102
• 57 Rohayem J, Haffner D, Cremers JF. et al. Testicular function in males with infantile nephropathic cystinosis. Hum Reprod 2021; 36: 1191-1204
• 58 Anikster Y, Lacbawan F, Brantly M. et al. Pulmonary dysfunction in adults with nephropathic cystinosis. Chest 2001; 119: 394-401
• 59 Trauner DA, Chase C, Scheller J. et al. Neurologic and cognitive deficits in children with cystinosis. J Pediatr 1988; 112: 912-914
• 60 Hohenfellner K, Harms E. Spezielle Cystinose-Sprechstunde. Dtsch Arztebl Ausg A 2015; 112: A-1378