Nephropathic cystinosis: late complications of a multisystemic disease

Abstract

Cystinosis is a rare autosomal recessive disorder due to impaired transport of cystine out of cellular lysosomes. Its estimated incidence is 1 in 100,000 live births. End-stage renal disease (ESRD) is the most prominent feature of cystinosis and, along with dehydration and electrolyte imbalance due to renal tubular Fanconi syndrome, has accounted for the bulk of deaths from this disorder. Prior to renal transplantation and cystine-depleting therapy with cysteamine for children with nephropathic cystinosis, their lifespan was approximately 10 years. Now, cystinotic patients have survived through their fifth decade, but the unremitting accumulation of cystine has created significant non-renal morbidity and mortality. In this article we review the classic presentation of nephropathic cystinosis and the natural history, diagnosis, and treatment of the disorder's systemic involvement. We also emphasize the role of oral cysteamine therapy in preventing the late complications of cystinosis.

Successful treatment of the murine model of cystinosis using bone marrow cell transplantation

“…4 Cystine crystals are found first in the periphery of the cornea and then in the center. 33 Ctns Ϫ/Ϫ mice demonstrate similar ocular anomalies to patients, 14,34 and cystine crystals are also first found at the periphery of the cornea.…”

“…In the third decade of life, patients with cystinosis exhibit a deterioration of the central nervous system characterized by mental deterioration, impaired cerebellar function, pyramidal signs, ischemic lesions, and severe impairment in visual short-term memory. 4 Middle-aged Ctns Ϫ/Ϫ mice also present with behavioral anomalies and spatial and working memory deficits that correlate with cystine accumulation in the brain. 14,35 In the present study, we demonstrated Ctns expressing BMC-derived cells in the brain, differentiated into or fused with endothelial or smooth muscle cells, as well as some glial-like cells.…”

“…38 Without cysteamine, cystinotic patients develop myopathy with atrophy and progressive distal extremity weakness as well as progressive oromotor dysfunction, including dysphagia. 4 Cystine crystals were observed in fibroblastic cells adjacent to muscle fibers and within perimysial collagen fibrils, and muscle necrosis was also observed. 39 The Ctns Ϫ/Ϫ mice also present with muscular impairment associated with cystine crystals located in interstitial cells and myocyte necrosis.…”

“…39 The Ctns Ϫ/Ϫ mice also present with muscular impairment associated with cystine crystals located in interstitial cells and myocyte necrosis. 14 Cardiomyopathy can be a late complication in cystinosis, 4 and one autopsy revealed the presence of cystine crystals in interstitial cardiac histiocytes and one myocardial cell. 40 Similarly, crystals were abundant in interstitial cells of Ctns Ϫ/Ϫ mice heart but not in myocytes.…”

“…2,3 Affected persons typically present before 2 years of age with symptoms of severe fluid and electrolyte disturbances (ie, dehydration, vomiting, poor growth, rickets). Without specific treatment, they progress to end-stage renal failure by the end of the first decade 4 ; in the United States, cystinosis accounts for approximately 1.4% of children on dialysis and 2% of pediatric kidney transplantations (North American Pediatric Renal Trials and Collaborative Studies, 2008 Annual Report). 5 Cystine accumulation eventually leads to multiorgan dysfunction and patients present with photophobia and blindness, hypothyroidism, hypogonadism, diabetes, myopathy, and central nervous system defects.…”