Cystinosis 2013: diagnosis, treatment, outcome

Elena Levtchenko, MD, PhD

Moscow, October 23, 2013

First description of cystinosis

Emil Abderhalden1877 - 1950

Early pregnancy test

Test for diagnosing cancer

Test for dementia praecox

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)

5

CTNS gene structure (17p13, 23 kb)

1 2 3c

44

5 6 7 8 9 10

11 12

ATG TAG

Cystinosin: predicted structure

GYDQLYFPQA

Chergui et al. 2001

Most common mutation in North European population: 57 kb deletion (Town et al. 1998)

6

nucleus

H+

H+

cystine

cystine

cysteine

lysosome

cytoplasma

cystinosin

protein degradation

cystine

cystine

cysteine

cysteine

N

C

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

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)

Nep

hro

pat

hic

cys

tin

osi

s

Clinical case

• 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

Length

Weight

Gradual development of Fanconi syndrome in cystinosis

age (months)

1 2 3 4 5 6 7 8

rena

l sym

ptom

s

aminoaciduria

glucosuria

phosphaturia

renal bicarbonate loss

full-blown Fanconi syndrome

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

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

14

Fair skin and hear 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

18

Cysteamine action

cystine

cytoplasm

cystinosin

lysosomeNH2 COOH

CH

CH2

S

S

CH2

CH

NH2 COOH

+

HS

CH2

CH2

NH2

SH

CH2

CH

NH2 COOH

NH2 COOH

CH

CH2

S

S

CH2

CH2

NH2

+

cystine cysteamine cysteinecysteine –cysteamine

cysteine transporter

*PQLC2-transporter

cytoplasm

lysosome

PQLC2

*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

1 2 3 4 5 6 hrs

cyst

ine

nmol

/mg

prot

ein

0.25

0.5

25

50

Cys

t eam

ine m

ol/l

Cystine in WBC < 0.5 nmol/mg protein (=1/2 cystine nmol/mg protein)

Markello et al. 1993

n= 67

n =

32

n = 17

1979-1984

0

5

10

15

20

1979-1984

0

10

20

30

40

1985-1990

0

5

10

15

201985-1990

0

10

20

30

40

1991-1996

0

5

10

15

201991-1996

0

10

20

30

40

1997-2002

0

5

10

15

201997-2002

0

10

20

30

40

2003-2008

0-1

2-3

4-5

6-7

8-9

10-1

1

12-1

3

14-1

5

16-1

7

18-1

90

5

10

15

20

2003-2008

0-1

2-3

4-5

6-7

8-9

10-1

1

12-1

3

14-1

5

16-1

7

18-1

90

10

20

30

40

Cystinosis patients Control patients

8.8

8.7

9.9

10.3

12.7

11.4

9.3

10.5

10.9

10.2

Age at start RRT

Van Stralen et al. CJASN 2011

Cystinosis Control

8.8

8.7

9.9

10.3

12.7

11.4

9.3

10.5

10.9

10.2

Data from ESPN/ERA-EDTA Registry

n = 245 (1-19 years old)

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

0 - 6 mo. 7 - 12 mo. 13 - 18 mo. 19 mo. - 5 yr. Over 5 yr.

7%

26%

39%

27%

2%

17%

33% 31%

18%

1%0%

11%

32%

43%

14%

North America Europe South America

72% and 81% of patients diagnosed before 18 months of age in North America and Europe, respectively (N=279)

43% in South America

Cure Cystinosis International Registry (CCIR): Age at diagnosis

Slow release cysteamine formulations

Released in

stomach

CystagonEnteric coated-

Cystagon

Released in duodenum

Delayed release

minmin min

Study design: phase 3 randomized crossover non-inferiority trial

Cystagon

2 weekRun-in

RP103 RP103

Cystagon Cystagon

3 weeks 3 weeks

DR Cysteamine

Extension Study3 tests/3 days

N = 41

WBC (<1 or 1<2)

PotentialDose Adjustment

• 43 patients randomized at 8 US and EU clinical sites; 41 completed• WBC cystine used in primary end point analysis

3 tests/3 days

3 tests/3 days

3 tests/3 days

PotentialDose Adjustment

Randomization

3 tests/3 days

- Additional WBC cystine and safety data will be collected during extension study

29

Cyst

eam

ine c

once

ntr

ati

on (

mg/L

)

WB

C C

yst

ine le

vel

(nm

ol ½

cyst

ine/m

g p

rote

in)

Time (min) Langman et al. CJASN 2012

Slow-release cysteamine (RP103) : equal efficiency to Cystagon®

WBC cystine : 0.62 ± 0.05 (RP103) versus 0.54 ± 0.05 (Cystagon®)after 3 weeks of treatment

Renal graft survival

Van Stralen et al. 2011

Cysteamine: adverse effects

Source: Orphan Europe (1996-2001)

Number of patients 363All side effects 84 (23%)

• Nausea - vomiting 57• Abdominal pain 20 • Bad odour and taste 24• Headache, asthenia 11• Anorexia 8• Dyspepsia 8• Torpor 4

Microscopy of elbow lesions

Besouw et al. 2011

Light microscopy (anti CD34-staining)

Electron microscopy

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

37

Extra-renal involvement

Eye– photophobia 50% 8-12 years – retinal blindness 10-15% 13-40 years

Endocrine organs– hypothyroidism 50% 5-10 years– diabetes mellitus 5% 18-40 years– male hypogonadism 70% 18-40 years

Neuromuscular disease– myopathy 20% 12-40 years

Neurological complaints 2-10% 21-40 years– Epilepsy mental deterioration– cerebella and pyramidal signs– stroke-like episodes Gahl et al. 2002

Cysteamine therapy prevents or postpones extra-renal complications (Nesterova et al. 2008)

Cystinotic band kerathopathy

Cystinotic retinopathy

Cystinotic distal myopathy

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

I. Bongaers

B. van den Heuvel

M. BesouwK. Ivanova S. Van Aerschot

NijmegenL. MonnensM. WilmerR. Masereuw

RomeF. EmmaA.Taranta

LondonW. van’t Hoff

ParisP. NiaudetC. AntignacS. Parker