Title: Longterm outcome of cystinosis
1Long-term outcome of cystinosis
- Elena Levtchenko, MD, PhD
- Department of Pediatric Nephrology
- Radboud University Medical Centre Nijmegen
- The Netherlands
Palermo, October 8th, 2006
2Definition
- Cystinosis autosomal recessive disorder caused
by lysosomal accumulation of cystine due to
mutations in CTNS gene (17p13) Town et al. 1998 - Cystinosis - "orphan" disease
- incidence 1 200,000 new-borns
- world-wide 2000 known individuals with
cystinosis
3nucleus
cystine
H
cysteine
cystinosin
H
cystine
lysosome
protein degradation
cytoplasma
Kalatzis et al. 2001
4Cystine accumulation in cystinosis
Kidney 200 - 400 x normal Liver 80 -
1000 x normal Muscle 40 - 70 x
normal Brain 5 - 20 x normal
5Cystinosis natural history
Birth No symptoms
Early infancy Fanconi syndrome Growth
retardation
Early childhood Photophobia
Late childhood Hypothyroidism ESRD ? death
6Superior renal graft survival in cystinosis
- No recurrence of cystinosis in renal graft
- Broyer et al. 1981, EDTA paediatric registry
n47 - 1 year patient and graft survival compared to
other primary renal diseases 89
versus 81 and 81 versus 67 - Kashtan et al. 1995, NAPRTCS data n83
- 2 year survival living-donor grafts 93,
cadaver donor grafts 71 -
- Niaudet, 2006, DIVAT, France n23
- 16 years graft survival in cystinosis 80 versus
65 in other primary renal
diseases
7Treatment with cysteamine
cystinosin
cytoplasm
cytoplasm
cysteine cysteamine
cystine
cysteamine
cysteine
lysosome
NH2 COOH CH CH2
S S CH2 CH NH2
COOH
NH2 COOH CH CH2
S S CH2 CH2
NH2
SH CH2 CH NH2
COOH
HS CH2 CH2 NH2
lysosome
cystine
cysteine transporter
8No treatment n 67
Partial treatment n 32 cysteamine started
after 2 years old, dose not always adequately
adapted
Adequate treatment n 17 cysteamine started
before 2 years old, dose adequately adapted
Markello et al. 1993
9Cystinosis changed history
Birth No symptoms
Early infancy Renal Fanconi syndrome Growth
retardation
Early childhood Photophobia
Late childhood Hypothyroidism ESRD ?
renal replacement
Adolescence and Nonrenal involvement
adulthood eye endocrine organs
muscles central neurvous system GI
tractus, liver, coronary arteries
10Ocular manifestations
Tsilou et al. 2002 and 2006
11Thyroid dysfunction
- Chernichov et al. 1970
- n15, age lt 16 years, 12/15 (80) hypothyroidism
- 9 compensated (? TSH, nl thyroxine), 3 overt
(?? TSH, ? thyroxine) - Tête et al. 1999 n55
-
free of thyroxine treatment
Cysteamine started lt 34 months of age
Cysteamine started between 4-7 years
Untreated
Age (years)
12Endocrine pancreas dysfunction
- Robert et al. 1999
- n44, post-transplant, follow-up 5.4-22.4 years,
145 OGTT
Insulin treatment
Patients free of symptoms ()
Diabetes at OGTT
Impaired glucose tolerance
Years after transplantation
13Growth retardation
- Kimonis et al. 1995 effect of cysteamine therapy
on growth - n101, aged 7 months - 36 years
Not treated Partially treated
Well treated
Height Z score - 4.070.39
- 3.040.33 - 2.170.39
Bone age deficit (yrs) 3.76
2.42 1.37
- No additional effect of concomitant cysteamine
therapy
14Gonadal dysfunction
- Chik et al. 1993
- 10 males, 15-28 years old, not
treated with cysteamine - no patient Tanner stage 5, reduced
testes volume, azospermia -
Testosterone (nmol/L)
Testosterone (nmol/L)
Luteinizing Hormone (IU/L)
Follicle Stimulating Hormone (IU/L)
- Broyer et al. 1995
- 18 females, menarche 14 - 22 years (mean 16.5
years) - Tete et al. 1999
- protective effect of cysteamine in females,
effect in males?
15Muscle dysfunction
- Charnas et al. 1994
- n54, 25 weakness and wasting of small hand
muscles, EMG normal nerve
conduction - muscle biopsy prominent vacuoles, type 1 fiber
atrophy, variations in fiber size - Dixit et al. 2002
- restrictive cardiomyopathy in a 33-year old
- heart tissue cystine 1000 x normal, cystine
crystals in myocytes and cardiac
histiocytes - Sonies et al. 2005
- n101, aged 6-45 years, on swallow barium
examination - oral, pharyngeal, esophageal swallowing
dysfunction - in 24, 51, 73 of patients
- severity of swallowing impairment increases with
age - cysteamine treatment prevents progression
16Respiratory dysfunction
- Anikster et al. 2001
- n12 (21-40 years), 11/12 restrictive ventilatory
defects, mean forced vital
capacity 5813 of predicted
- Edens et al. 2006
- respiratory dysfunction due to diaphragm
myopathy in a 38-year old - successful treatment with nocturnal
non-invasive positive pressure
ventilation (NIPPV)
17Central nervous system dysfunction
- Broyer et al. 1996 n43, 10/43 encephalopathy
(19-26 years) - type 1 cerebellar and pyramidal signs, mental
deterioration, pseudo bulbar palsy - type 2 ischemic cerebral stroke
- Brain imaging cerebral atrophy, calcifications
of diverse brain regions, - tumor-like changes
- Cysteamine treatment beneficial
- Intellectual deficits
- Lower IQ compared to parents and siblings
(Williams et al. 1994) - Visual processing deficit (Ballantyne et al.
1997) - Difficulties in tactile recognition (Colah et al.
1997) - Discrepancy between verbal IQ and performal IQ
(Hulstijn et al. 2006) - Idiopathic intracranial hypertension (Dogulu et
al. 2004)
18Other nonrenal complications of cystinosis
- Liver disease
- hepatosplenomegaly, portal hypertension,
hypersplenism - sever nodular regenerative hyperplasia (OBrien
et al. 2006) - Exocrine pancreas deficiency (Fivush et al. 1988)
- Coronary arteries involvement
- dilatation (Olgar et al. 2006)
- calcifications (Gahl et al. 2005)
19New adverse effects of cysteamine (Cystagon)6
cases (aged 5-15 years) reported in 2004-2006
among 550 patients in the EU
20Adverse effects of cysteamine (Cystagon)
- Skin lesions 6/6
- elbow lesions (bruising), striae
- LM extensive proliferation of capillaries -
angioendotheliomatosis - EM fragmentation and desorganisation of collagen
fibres - Bone lesions 4/6
- pain, weakness, periosteal reactions, thickening
of trabecular bone - Cerebral lesions 1/6
- acute cerebral ischemia due to vascular changes
- Cysteamine dose gt 80 mg/kg/day 3/6
- Mechanism of adverse event?
- interaction between cysteamine and disulfide
bridges of collagen - increased susceptibly to cysteamine toxicity
21Approved Changes in Cystagon posology
- For children up to age 12 years, Cystagon dosing
should be done on the basis of body surface area
(g/m2/day). The recommended dose is 1.30
g/m2/day in 4 times daily - For patients over age 12 and over 50 kg weight,
the recommended Cystagon dose is 2
g/day in 4 times daily - The use of doses higher than 1.95 g/m2/day is not
recommended - REPORT ANY SUSPECTED ADVERSE REACTION TO
ORPHAN EUROPE(pharmacovigilance_at_orphan-europe.com)
22Conclusions
- Longer survival of patients with cystinosis
revealed multiple non-renal complications of the
disease - Cysteamine should be administered to all
(non-pregnant) cystinosis patients - protection of renal function
- prevention or delay of non-renal complications
- Detection of a new adverse event led to a
re-assessment of the safety profile and to
adjustment of posology for cysteamine
(Cystagon). Risk/benefit ratio of Cystagon is
favourable. - Future prospective European Cystinosis Registry
(W. vant Hoff)
23Cystinosis research group Nijmegen
Prof. Dr. L. Monnens Dr. B. van den Heuvel Ing.
M. Wilmer Dr. H. Blom A. De Graaf-Hess