Longterm outcome of cystinosis

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Long-term outcome of cystinosis

• Elena Levtchenko, MD, PhD
• Department of Pediatric Nephrology
• Radboud University Medical Centre Nijmegen
• The Netherlands

Palermo, October 8th, 2006
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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

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

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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
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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
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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
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Ocular manifestations
Tsilou et al. 2002 and 2006
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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)
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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
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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

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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?

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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

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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)

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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)

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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)

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

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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)
  

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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)

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