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Longterm outcome of cystinosis

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Title: Longterm outcome of cystinosis


1
Long-term outcome of cystinosis
  • Elena Levtchenko, MD, PhD
  • Department of Pediatric Nephrology
  • Radboud University Medical Centre Nijmegen
  • The Netherlands

Palermo, October 8th, 2006
2
Definition
  • 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

3
nucleus
cystine
H
cysteine
cystinosin
H
cystine
lysosome
protein degradation
cytoplasma
Kalatzis et al. 2001
4
Cystine accumulation in cystinosis
Kidney 200 - 400 x normal Liver 80 -
1000 x normal Muscle 40 - 70 x
normal Brain 5 - 20 x normal
5
Cystinosis natural history
Birth No symptoms
Early infancy Fanconi syndrome Growth
retardation
Early childhood Photophobia
Late childhood Hypothyroidism ESRD ? death
6
Superior 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

7
Treatment 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
8
No 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
9
Cystinosis 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
10
Ocular manifestations
Tsilou et al. 2002 and 2006
11
Thyroid 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)
12
Endocrine 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
13
Growth 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

14
Gonadal 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?

15
Muscle 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

16
Respiratory 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)

17
Central 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)

18
Other 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)

19
New adverse effects of cysteamine (Cystagon)6
cases (aged 5-15 years) reported in 2004-2006
among 550 patients in the EU
20
Adverse 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

21
Approved 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)

22
Conclusions
  • 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)

23
Cystinosis research group Nijmegen
Prof. Dr. L. Monnens Dr. B. van den Heuvel Ing.
M. Wilmer Dr. H. Blom A. De Graaf-Hess
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