Natural history of adolescent-onset cystinosis
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BRIEF REPORT
Natural history of adolescent-onset cystinosis Julian P. Midgley & Reyhan El-Kares & François Mathieu & Paul Goodyer
Received: 17 January 2011 / Revised: 4 April 2011 / Accepted: 5 April 2011 / Published online: 8 May 2011 # IPNA 2011
Abstract Cystinosis is a rare autosomal recessive disease caused by mutations of the CTNS gene in which cystine accumulates throughout the body as a result of a defective efflux of cystine from lysosomes. Three phenotypic forms have been described according to the age of onset and the severity of the clinical symptoms: infantile, intermediate, and ocular non-nephropathic cystinosis. Here we report the natural history of cystinosis in a 55-year-old man with intermediate nephropathic cystinosis diagnosed at 9 years of age. Although tubulopathy was unnoticed in the early years, he required transplantation at age 16. Sequencing analysis of all the CTNS exons revealed that the proband is homozygous for a 21-bp inframe deletion in exon 5 (c. 198_218del21), resulting in an inframe deletion of 7 amino acids from the N-terminal domain of the cystinosin protein. Our patient has had relatively mild extra-renal disease despite lack of early cysteamine therapy. He has been able to attend university and pursue a professional career into the 6th decade. Keywords Cystinosis . Nephropathic cystinosis . CTNS . Cystinosin . Cysteamine J. P. Midgley Departments of Pediatrics, Alberta Children’s Hospital, 2888 Shaganappi Trail, NW, Calgary, AB T3B 6A8, Canada R. El-Kares : F. Mathieu : P. Goodyer Department of Pediatrics, McGill University, Montreal Children’s Hospital Research Institute, 4060 Ste Catherine west, Montreal, QC, Canada H3Z 2Z3 P. Goodyer (*) Montreal Children’s Hospital, 2300 Tupper Street, Montreal, QC, Canada H3H 1P3 e-mail: [email protected]
Introduction Cystinosis is a rare autosomal recessive disease caused by mutations in the CTNS gene, encoding cystinosin, a transport protein that mediates efflux of cystine from the lysosome [1]. Patients with null mutations of CTNS have complete loss of cystinosin function and develop the infantile form of cystinosis (OMIM #219800) with emergence of renal tubular Fanconi syndrome by 6–12 months of age. During the first year of life, they exhibit failure to thrive, renal salt wasting with polyuria, acidosis, and hypophosphatemic rickets. Over the first decade, the children develop photophobia, hypothyroidism, and progressive glomerular damage. By ∼10–11 years of age, most children develop end-stage renal disease and require dialysis and/or renal transplantation. Although graft survival is excellent, the second decade is dominated by distal vacuolar myopathy, retinal blindness, swallowing difficulty, diabetes mellitus, and neurological deterioration [2]. The introduction of oral cysteamine therapy has altered the natural history of cystinosis, ameliorating progressive thyroid failure and delaying the onset of end-stage renal disease. However, it is unclear whether cysteamine therapy can extend longevity beyond 30 years of age. Mild
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