6-1. Cystinosis. Elena Levtchenko (eng)

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6-1. Cystinosis. Elena Levtchenko (eng)

  1. 1. Cystinosis 2013: diagnosis, treatment, outcome Elena Levtchenko, MD, PhD Moscow, October 23, 2013
  2. 2. First description of cystinosis Early pregnancy test Test for diagnosing cancer Test for dementia praecox Emil Abderhalden 1877 - 1950 Abderhalden E. Familiäre Cystindiathese. Z. Physiol Chem 38: 557-561, 1903
  3. 3. Cystinosis – an autosomal recessive disease caused by lysosomal accumulation of cystine due to defective exodus of cystine out of the lysosomes – Orphan disease: incidence ~1:100,000-200,000 (clustering in some populations) – most common cause of inherited generalized proximal tubular dysfunction (renal Fanconi syndrome)
  4. 4. CTNS gene structure (17p13, 23 kb) TAG ATG 1 2 3 c 4 4 5 6 7 8 9 10 11 12 Cystinosin: predicted structure YFPQA GYDQL Chergui et al. 2001 5 Most common mutation in North European population: 57 kb deletion (Town et al. 1998)
  5. 5. nucleus cystine cystine H+ cysteine C cystine cysteine N cystinosin H+ cystine protein degradation cytoplasma 6 cystein e lysosom e
  6. 6. Cystine accumulation in cystinosis Kidney: 200 - 400 x normal Liver: 80 - 1000 x normal Muscle: 40 - 70 x normal Brain: 5 - 20 x normal Gahl et al. 2001
  7. 7. Nephropathic cystinosis Clinical forms • Infantile form (>90%): – Fanconi syndrome ~ 3-6 months – end stage renal disease (ESRD) ~ 10 years • “Late-onset” (juvenile) form (~5%): – later onset (often during puberty) – mild tubulopathy, more pronounced proteinuria, (even in nephrotic range) – later progression to ESRD • Ocular form • Overlap between ocular and juvenile forms (Servais et al. 2008) 8
  8. 8. Clinical case Length • • • • • Born after 40 weeks normal pregnancy Birth weight 3200g No symptoms up to 6 months 6-9 months: failure to thrive, vomiting, slowed development 9 months: diagnosis of renal Fanconi syndrome due to CYSTINOSIS Weight
  9. 9. Gradual development of Fanconi syndrome in cystinosis renal symptoms full-blown Fanconi syndrome renal bicarbonate loss phosphaturia glucosuria aminoaciduria 1 2 3 4 5 age (months) 6 7 8 Levtchenko et al. 2006
  10. 10. Biochemical symptoms of « full-blown » Fanconi syndrome • Generalized dysfunction of renal proximal tubules: – – – – – – – – – – Polyuria Aminoaciduria Glucosuria Phosphaturia Na+, K+ , HCO3- losses Hypercalciuria Low molecular weight proteinuria, albuminuria Hyperuricosuria Carnitinuria Other solutes reabsorbed in renal proximal tubules
  11. 11. Clinical symptoms of renal Fanconi syndrome • • • • • • Failure to thrive/growth retardation Vomiting Constipation Dehydration Rickets Developmental delay/hypotony
  12. 12. Diagnosis of cystinosis • Suspected clinical presentation – cystinosis - most common cause of Fanconi syndrome • Measurement of elevated cystine content in granulocytes: – – – – – Controls < 0.3 nmol ½ cystine/mg protein Heterozygotes < 1 nmol ½ cystine/mg protein Patients at diagnosis > 2 nmol ½ cystine/mg protein Patients on cysteamine therapy < 1 nmol ½ cystine/mg protein Values of your own laboratory! • Cystine crystals in cornea (>1 year) • Molecular analysis of cystinosis gene 13
  13. 13. Fair skin and hear 14 Rickets at presentation Corneal cystine crystals
  14. 14. Treatment of cystinosis • Symptomatic: – – – – free access to water and toilet replacement of urinary losses due to renal Fanconi syndrome indomethacin hormone replacement when required (thyroxin, insulin, testosterone) – growth hormone in children with poor growth • Specific treatment with cysteamine
  15. 15. Symptomatic treatment (1) • Potassium: – K citrate (high doses can be required) – KCl • Alcali: – K citrate – (Na bicarbonate) • Phosphate: – NaK Phosphate – Phosphate Sandoz (1tabl: P 16 mmol, Na 20 mmol, K 3mmol) – dose phosphate < 50 mg/kg/day (<1.6 mmol/kg/day) • (NaCl) rarely required
  16. 16. Symptomatic treatment (2) • 25(OH)vit D • 1,25(OH)2vitD (if required) • Carnitine < 50mg/kg/day in x3 – monitor plasma concentration and profile • Indomethacin 0.5-1mg/kg/day in x2 – monitor kidney function – discontinue > 2-3 years – avoid combination with ACE inhibitors
  17. 17. Cysteamine action cystinosin cytoplasm cytoplasm cystine NH2 cysteamine cysteine – cysteamine cysteine PQLC2 COOH CH CH CH2 CH2 CH2 CH2 CH HS S + S CH2 NH2 NH2 CH NH2 COOH COOH SH CH2 lysosome lysosome NH2 cystine COOH + S S CH2 *PQLC2transporter CH2 NH2 cysteine transporter 18 *Jézégou et al. 2012
  18. 18. Cysteamine administration • Dose: 1.3 g/m2/day in x4 (max 1.9 g/m2/day, adults 2g/day) • Administration every 6 hours • Start 1/6 – ¼ daily dose  gradually increase the dose during 6-8 weeks • In case of nausea, abdominal pain: decrease the dose for 1 week, and then try to increase again • Use PPI if required • Monitoring treatment: children x4 per year, adults x2 per year; value 6 hours after dose in heterozygous range
  19. 19. Monitoring of cysteamine therapy 0.5 50 0.25 25 1 2 3 4 5 6 hrs Cystine in WBC < 0.5 nmol/mg protein (=1/2 cystine nmol/mg protein)
  20. 20. n= 67 n= 32 n = 17 Markello et al. 1993
  21. 21. 20 Control Control patients 40 1979-1984 8.8 8.8 15 10 10 0 0 40 20 1985-1990 8.7 8.7 15 9.3 30 20 5 10 0 20 0 40 1991-1996 9.9 9.9 15 1991-1996 10.5 10.5 30 10 20 5 10 0 20 0 40 10.3 10.3 15 10.9 1997-2002 10.9 30 10 10 0 1997-2002 20 5 0 40 20 12.7 12.7 15 2003-2008 10.2 10.2 30 18-19 16-17 14-15 12-13 10-11 8-9 6-7 4-5 2-3 18-19 16-17 14-15 12-13 10-11 8-9 0 6-7 0 4-5 10 2-3 5 2003-2008 20 0-1 10 Van Stralen et al. CJASN 2011 1985-1990 9.3 10 Age at start RRT 11.4 1979-1984 20 5 n = 245 (1-19 years old) 11.4 30 0-1 Data from ESPN/ERAEDTA Registry Cystinosis Cystinosis patients
  22. 22. Eunefron Cystinosis Registry 2012 Decade of Birth Median Kidney survival (years) 1970s 11.8 1980s 12.9 1990s 16.6 The 10 year survival of an affected individual born in the 1990s is significantly better than that of an individual born in 1980s (p = 0.0313; Odds ratio for survival = 2.4, 95% CI = 1.13 to 4.90). Van’t Hoff, Niaudet, Levtchenko, Antignac, Greco, Parker, Emma. EUNEFRON
  23. 23. Reasons for lower than expected efficacy of cysteamine • Delay in the diagnosis of cystinosis (delay in cysteamine therapy) • Non-compliance with cysteamine therapy: – Difficult dose regimen (4 times daily): • < 25% of the patients follow the prescription (Levtchenko et al. 2006) – Gastro-intestinal complaints (Dohil et al. 2003) – Bad breath and sweat odor (Besouw et al. 2007) • Possibly not all down-stream effect of cystinosin dysfunction (beyond cystine accumulation) are corrected by cysteamine
  24. 24. Renal survival depends on cystine depletion Van’t Hoff et al. EUNEFRON conference 2012
  25. 25. Cure Cystinosis International Registry (CCIR): Age at diagnosis North America Europe South America 43% 39% 33% 31% 32% 27% 26% 18% 17% 14% 11% 7% 2% 1% 0% 0 - 6 mo. 7 - 12 mo. 13 - 18 mo. 19 mo. - 5 yr. Over 5 yr.  72% and 81% of patients diagnosed before 18 months of age in North America and Europe, respectively (N=279)  43% in South America
  26. 26. Slow release cysteamine formulations Cystagon Released in stomach min Enteric coatedCystagon Delayed release Released in duodenum min min
  27. 27. Study design: phase 3 randomized crossover non-inferiority trial • 43 patients randomized at 8 US and EU clinical sites; 41 completed • WBC cystine used in primary end point analysis - Additional WBC cystine and safety data will be collected during extension study RP103 Potential Dose Adjustment RP103 3 tests/ 3 days Potential Dose Adjustment 3 tests/ 3 days DR Cysteamine Cystagon 3 tests/ 3 days Randomization Extension Study 2 week Run-in N = 41 WBC (<1 or 1<2) Cystagon 3 tests/ 3 days 3 weeks Cystagon 3 tests/ 3 days 3 weeks
  28. 28. Slow-release cysteamine (RP103) : equal efficiency to Cystagon® WBC Cystine level (nmol ½ cystine/mg protein) Cysteamine concentration (mg/L) WBC cystine : 0.62 ± 0.05 (RP103) versus 0.54 ± 0.05 (Cystagon®) after 3 weeks of treatment Time (min) 29 Langman et al. CJASN 2012
  29. 29. Renal graft survival Van Stralen et al. 2011
  30. 30. Cysteamine: adverse effects Number of patients All side effects • • • • • • • Nausea - vomiting Abdominal pain Bad odour and taste Headache, asthenia Anorexia Dyspepsia Torpor 363 84 (23%) 57 20 24 11 8 8 4 Source: Orphan Europe (1996-2001)
  31. 31. Microscopy of elbow lesions Light microscopy (anti CD34staining) Electron microscopy Besouw et al. 2011
  32. 32. Cysteamine increases proliferation of human dermal microvascular endothelial cells (HDMVEC) Cell proliferation (BrDU) Apoptosis (Caspase 3) Besouw et al. Submitted
  33. 33. Proposed mechanism of collagen lesions in patients with cysteamine toxicity Copper suppletion might prevent the development of cysteamine toxicity in patients with Fanconi syndrome (cholorophyl 1 tabl: 4 mg copper) Besouw et al. Submitted
  34. 34. Extra-renal involvement Eye – photophobia – retinal blindness 50% 10-15% 8-12 years 13-40 years Endocrine organs – hypothyroidism – diabetes mellitus – male hypogonadism 50% 5% 70% 5-10 years 18-40 years 18-40 years Neuromuscular disease – myopathy 20% 12-40 years 2-10% 21-40 years Neurological complaints – Epilepsy mental deterioration – cerebella and pyramidal signs – stroke-like episodes Gahl et al. 2002 Cysteamine therapy prevents or postpones extra-renal 37 complications (Nesterova et al. 2008)
  35. 35. Cystinotic band kerathopathy Cystinotic distal myopathy Cystinotic retinopathy Cystinotic cortical athrophy
  36. 36. Follow-up of cystinosis patients: multi-disciplinary approach • Children: every 3 months – – – – growth, feeding, biochemical parameters adjusting symptomatic treatment adjusting cysteamine dose according to WBC cystine levels eye examination: yearly • Adults: yearly – adjusting cysteamine dose according to WBC cystine levels – special attention to extra-renal complications: • eye examination, thyroid testing, glucose tolerance, muscular strength, lung function, bone densitometry, genetic counseling/family planning
  37. 37. Cystinosis 2013: 110th anniversary • Enormous progress is made in understanding molecular basis and treatment of cystinosis • Dramatic improvement of prognosis in cystinosis patients with current life expectancy extending 50 years old • Novel therapies based on better understanding disease physiology are emerging
  38. 38. Acknowledgments Nijmegen L. Monnens M. Wilmer R. Masereuw Rome F. Emma A.Taranta B. van den Heuvel K. Ivanova I. Bongaers M. Besouw S. Van Aerschot London W. van’t Hoff Paris P. Niaudet C. Antignac S. Parker

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