Nephropathic Cystinosis
Cystinosis – The Post-transplant Era
William A Gahl1 and Galina Nesterova2
1. Clinical Director, National Human Genome Research Institute, and Director, Intramural Program, Office of Rare Diseases, National Institutes of Health; 2. Clinical/Biochemical Genetics Fellow, Section on Human Biochemical Genetics Intramural Program, Office of Rare Diseases, National Institutes of Health
Abstract
The lysosomal storage disease cystinosis provides an excellent example of success in the treatment of a previously lethal genetic disease. In recent decades, nephropathic cystinosis (NC) has changed in its clinical course from a fatal renal disease to a chronic multisystemic disorder. Survival and lifespan have increased dramatically due to renal transplantation and the availability of cystine-depleting therapy with cysteamine. The importance of recognising the diagnosis of cystinosis cannot be overemphasised, since virtually all vital organ systems affected by cystinosis can benefit from cysteamine therapy. This article will review the post-transplant course of NC and the detection, prevention and treatment of its serious complications.
Keywords
Cystinosis, nephropathic, transplant, complications, cysteamine
Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: This study was supported by the Intramural Program of the National Human Genome Research Institute. Received: 20 January 2010 Accepted: 16 March 2010 Citation: European Nephrology, 2010;4:55–61 Correspondence: William A Gahl, National Institutes of Health, 10 Center Drive – MSC 1851, Building 10, Room 10C-103, Bethesda, MD 20892-1851, US. E:
bgahl@helix.nih.gov
Cystinosis is a rare but important autosomal recessive storage disorder resulting from deficiency of the lysosomal membrane transporter cystinosin. As a consequence, tissues accumulate variable amounts of the disulphide amino acid cystine. Cystinosis occurs in all ethnic groups, with an overall incidence of approximately one in 100,000–200,000 live births. Three overlapping clinical phenotypes are recognised, varying in severity and age of onset. The most severe, an infantile, nephropathic form (MIM 219800), appears in the first year of life. A juvenile, late-onset or adolescent form (MIM 219900) is also nephropathic, while ocular, non-nephropathic cystinosis manifests largely with corneal crystal deposition (MIM 219750). Approximately 95% of all cystinosis patients have nephropathic cystinosis (NC).1
Prior to the era of successful renal
transplantation, the typical cystinosis patient had a mean lifespan of nine to 10 years due to progressive renal failure;2
even today, with renal
transplantation, NC patients not treated with chronic cystine-depleting therapy have a 33% mortality rate, with a mean age at death of approximately 29 years.3
Renal transplantation and successful treatment
targeting the basic metabolic defect have favourably altered the natural history of NC, often eliminating the need for dialysis and enabling patients to enjoy an improved lifestyle; life expectancy extends beyond the fifth decade.4
However, serious dysfunctions of various organ
systems are emerging as major complications due to the continuous accumulation of cystine in virtually every tissue.
History
NC was first described at the beginning of the 20th century. From the 1930s, it was known as a generalised renal tubular disorder,
i.e.
Debré–de Toni–Fanconi syndrome. In the 1960s, clinical investigations into cystinosis revealed that cystine accumulates intracellularly in
© T O UCH BRIEFINGS 2010
Genetics
Cystinosin is encoded by the gene CTNS, which contains 12 exons and 23kb of genomic DNA. More than 60 CTNS mutations have been described, many of them private. However, the most common
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lysosomes, with normal plasma cystine concentrations. Fundamental advances in the understanding of the genetics and pathophysiology of cystinosis as a lysosomal transport disorder have been achieved in the past three decades.
Basic Defect
In 1982, the transport of cystine from the lysosome to the cytoplasm was characterised as the first example of a small molecule carrier in the lysosomal membrane.5
In 1998, discovery of the gene CTNS led to fuller
characterisation of the structure of the cystine transporter cystinosin, with its 367 amino acids and seven transmembrane domains. Cystinosin is localised to the lysosomal membrane through one or more targeting signals.6
The protein, when mutated, has different amounts of
residual capacity for cystine efflux from lysosomes, correlating somewhat with clinical severity;7
leukocyte cystine levels also reflect
disease severity. CTNS-/- knockout mice exhibit cystine concentrations that increase with age and differ significantly from tissue to tissue.8
Cystine is poorly soluble and forms crystals in various cell types, but not in leukocytes (except macrophages) or cultured fibroblasts. Cystinosis cells display an increased rate of apoptosis, as cystine interacts with pro-apoptotic proteins in the cytosol.9
Poly-morphonuclear phagocytes
have altered oxidative metabolism, with increased free radical production due to cystine accumulation.
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