Post on 30-Nov-2014
description
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