Nephropathic Cystinosis
Nephropathic Cystinosis in Adolescents and Adults Aude Servais,1
Albane Brodin-Sartorius,1 Corinne Antignac3
Marie-Joseph Tête,1 and Jean-Pierre Grünfeld2
1. Nephrologist, Department of Nephrology, Necker-Enfants Malades Hospital and University of Paris Descartes; 2. Professor, Department of Nephrology, Necker-Enfants Malades Hospital and University of Paris Descartes; 3. Professor, University of Paris Descartes, Department of Genetics, Necker-Enfants Malades Hospital and INSERM U574
Philippe Lesavre,2
Abstract
Cystinosis is a multisystem autosomal recessive disease characterised by the intra-lysosomal accumulation of cystine, due to a defect in cystine transport across the lysosomal membrane. Three clinical forms have been described based on severity of symptoms and age of onset: infantile cystinosis, characterised by renal proximal tubulopathy and progression to end-stage renal disease before 12 years of age; the juvenile form, with a markedly slower rate of progression; and the adult form, with mainly – but not only – ocular abnormalities. Cysteamine treatment significantly delays the onset of end-stage renal disease, hypothyroidism, diabetes and neuromuscular disorder, and increases the life expectancy of cystinotic patients. In patients with non-infantile cystinosis, nephropathic cystinosis may be difficult to diagnose. In such cases, renal involvement is heterogeneous even within families, and renal disease should be assessed even in families of patients with apparently isolated ocular forms.
Keywords Cystinosis, CTNS gene, cystinosin, renal failure, end-stage renal disease, cysteamine
Disclosure: The authors have received research support from Orphan Europe for their work. Received: 6 December 2011 Accepted: 16 January 2012 Citation: European Nephrology, 2012;6(1):42–6 Correspondence: Aude Servais, Department of Nephrology, Necker Hospital, 149 rue de Sèvres, 75015 Paris, France. E:
aude.servais@
nck.aphp.fr
Support: The publication of this article was funded by Orphan Europe. The views and opinions expressed are those of the authors and not necessarily those of Orphan Europe.
Cystinosis is an autosomal recessive lysosomal storage disease caused by a defect in the carrier-mediated system that normally transports cystine out of lysosomes. CTNS, the gene mutated in cystinosis, maps to chromosome 17p13. CTNS mutations have been detected in almost all children with nephropathic infantile cystinosis. More than 90 different CTNS mutations have been described, but approximately 75 % of the CTNS mutations of European descent carry a homozygous ~57 kb deletion encompassing CTNS exons 1–10.1–4
The CTNS gene encodes
cystinosin, which transports the disulfide amino acid cystine out of lysosomes into cytoplasm, where it is reduced to cysteine.2,5 Its defect results in intralysosomal cystine accumulation, crystal formation and progressive organ damage.6
Infantile cystinosis, also known as nephropathic infantile cystinosis, is the most common form of cystinosis. Affected children usually develop renal proximal tubulopathy (or Fanconi syndrome) between six and 12 months of age. In the absence of treatment, renal failure occurs, with progression to end-stage renal disease (ESRD) at about nine years of age.7
Renal histopathological changes in infantile
nephropathic cystinosis include severe lesions of proximal tubules, typical alterations to the glomerular podocytes (which become multinucleated giant cells) and the presence of cystine crystals, mostly in interstitial cells and podocytes.8
The proximal tubule is the
first clinical target of the disease, but cystine crystals are rarely found in the tubular cells of cystinotic patients.
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It has been shown that renal transplantation markedly improves the lifespan of cystinotic patients.9
However, cystine accumulation
continues in non-renal organs. Consequently, the clinical course of cystinosis changes from that of a largely renal disease to a multisystem disorder. Indeed, cystine crystal deposition in the cornea leads to photophobia, and continuous widespread cystine accumulation eventually leads to rickets and to retinal, endocrinological (hypothyroidism and impaired glucose tolerance), hepatic, gastrointestinal, muscular and neurological abnormalities. In this article, we will focus on cystinosis in adolescents and adults, including late onset nephropathic cystinosis.
Impact of Cysteamine Treatment
Cysteamine is the only cystine-depleting drug available. It helps to eliminate cystine from lysosomes, and slows down renal deterioration and other organ dysfunctions.10
However, little is known about the
long-term progression of nephropathic cystinotic patients since cysteamine treatment has become available.
Gahl et al. have recently described the natural history of nephropathic cystinosis in a cohort of 100 adults and demonstrated that long-term oral cysteamine therapy mitigates the effects of the disease.11
The
outcomes of 10 Dutch cystinotic adults have been studied, but no uniform treatment strategy had been applied in these patients.12
In
1995, Broyer et al. described a cohort of 33 cystinotic French adults, but only five of them were under treatment at the time of the study.13
© TOUCH BRIEFINGS 2012
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