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. 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)
5. 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)
7. 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
8. 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
9. 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
10. 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
13. 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
14. Fair skin and hear
14
Rickets at presentation
Corneal cystine crystals
15. 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
16. 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
17. 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
19. 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
20. 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)
23. 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
24. 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
26. 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
27. Slow release cysteamine formulations
Cystagon
Released
in
stomach
min
Enteric
coatedCystagon
Delayed
release
Released
in
duodenum
min
min
28. 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
29. 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
31. 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)
34. Microscopy of elbow lesions
Light microscopy
(anti CD34staining)
Electron
microscopy
Besouw et al. 2011
35. Cysteamine increases proliferation of human dermal
microvascular endothelial cells (HDMVEC)
Cell
proliferation
(BrDU)
Apoptosis
(Caspase 3)
Besouw et al. Submitted
36. 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
37. 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)
39. 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
40. 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
41. 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