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Cystinosis 2013:
diagnosis, treatment, outcome
Elena Levtchenko, MD, PhD
Moscow, October 23, 2013
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
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)
6-1. Cystinosis. Elena Levtchenko (eng)
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)
nucleus
cystine
cystine

H+
cysteine

C

cystine
cysteine

N

cystinosin

H+

cystine
protein
degradation
cytoplasma

6

cystein
e
lysosom
e
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
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
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
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
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
Clinical symptoms of renal Fanconi
syndrome
•
•
•
•
•
•

Failure to thrive/growth retardation
Vomiting
Constipation
Dehydration
Rickets
Developmental delay/hypotony
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
Fair skin and hear

14

Rickets at presentation

Corneal cystine crystals
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
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
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
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
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
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)
n= 67

n=
32

n = 17

Markello et al. 1993
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
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
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
Renal survival depends on cystine depletion

Van’t Hoff et al. EUNEFRON conference 2012
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
Slow release cysteamine formulations

Cystagon

Released
in
stomach

min

Enteric
coatedCystagon

Delayed
release

Released
in
duodenum

min

min
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
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
Renal graft survival

Van Stralen et al. 2011
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)
6-1. Cystinosis. Elena Levtchenko (eng)
6-1. Cystinosis. Elena Levtchenko (eng)
Microscopy of elbow lesions

Light microscopy
(anti CD34staining)

Electron
microscopy
Besouw et al. 2011
Cysteamine increases proliferation of human dermal
microvascular endothelial cells (HDMVEC)

Cell
proliferation
(BrDU)

Apoptosis
(Caspase 3)

Besouw et al. Submitted
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
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)
Cystinotic band
kerathopathy

Cystinotic distal myopathy

Cystinotic retinopathy

Cystinotic cortical athrophy
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
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
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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6-1. Cystinosis. Elena Levtchenko (eng)

  • 1. Cystinosis 2013: diagnosis, treatment, outcome Elena Levtchenko, MD, PhD Moscow, October 23, 2013
  • 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
  • 11. 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
  • 12. Clinical symptoms of renal Fanconi syndrome • • • • • • Failure to thrive/growth retardation Vomiting Constipation Dehydration Rickets Developmental delay/hypotony
  • 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)
  • 21. n= 67 n= 32 n = 17 Markello et al. 1993
  • 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
  • 25. Renal survival depends on cystine depletion Van’t Hoff et al. EUNEFRON conference 2012
  • 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
  • 30. Renal graft survival Van Stralen et al. 2011
  • 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)
  • 38. Cystinotic band kerathopathy Cystinotic distal myopathy Cystinotic retinopathy Cystinotic cortical athrophy
  • 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