Cystinosis

There are numerous abnormalities of cysteine metabolism. Cystine, lysine, arginine, and ornithine are excreted in cystine-lysinuria (cystinuria), a defect in renal reabsorption. Apart from cystine calculi, cystinuria is benign. The mixed disulfide of L-cysteine and L-homocysteine (Figure 30-9) excreted by cystinuric patients is more soluble than cystine and reduces formation of cystine calculi. Several metabolic defects result in vitamin Bg-responsive or -unresponsive ho-mocystinurias. Defective carrier-mediated transport of cystine results in cystinosis (cystine storage disease) with deposition of cystine crystals in tissues and early mortality from acute renal failure. Despite... 

Neuronal ceroid lipofuscinosis (CNL5) Danon s disease (LAMP-2 deficiency) Niemann-Pick disease C type 1 Cystinosis... 

Globoid leukodystrophy Metachromatic leukodystrophy X-linked adrenoleukodystrophy Refsum s disease Cystinosis... 

In some cases, the amino acid pattern on a paper chromatogram is very similar to that found in diseases of the renal tubules, such as cystinosis, where there is a failure to reabsorb all amino acids from the glomerular filtrate and, in consequence, the urinary amino acid pattern resembles that of plasma (W6, W9). In other cases the aminoaciduria is less marked and the amino acids found in greatest excess are glycine, alanine, serine, threonine, and glutamine. In some cases no aminoaciduria has been detected. 

Cysteamine (/3-mercapto-ethylamine) is used for the treatment of nephropathic cystinosis. Cysteamine converts within lysosomes cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome thus removing the extra cystine. After oral administration peak plasma levels are reached at about 1.4 hours post dose. It is eliminated as a sulfate in the urine with a half-life of 4-5 hours. The most frequent adverse reactions seen involve the gastrointestinal and central nervous systems. Side effects include abdominal pain, diarrhea, drowsiness, fever, loss of appetite, nausea or vomiting and skin rash. Confusion, dizziness and headache may occur. 

Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults natural history and effects of oral cysteamine therapy. Ann Intern Med 2007 147(4) 242-50. 

Cysteine and cystine are relatively insoluble and are toxic in excess.450 Excretion is usually controlled carefully. However, in cystinuria, a disease recognized in the medical literature since 1810,451 there is a greatly increased excretion of cystine and also of the dibasic amino acids.451 452 As a consequence, stones of cystine develop in the kidneys and bladder. Patients may excrete more than 1 g of cystine in 24 h compared to a normal of 0.05 g, as well as excessive amounts of lysine, arginine, and ornithine. The defect can be fatal, but some persons with the condition remain healthy indefinitely. Cystinuria is one of several human diseases with altered membrane transport and faulty reabsorption of materials from kidney tubules or from the small intestine. Substances are taken up on one side of a cell (e.g., at the bottom of the cell in Fig. 1-6) and discharged into the bloodstream from the other side of the cell. In another rare hereditary condition, cystinosis, free cystine accumulates within lyso-somes.453... 

Wuhl E, Haffner D, Offner G, Broyer M, van t Hoff W, Mehls OEuropean Study Group on Growth Hormone Treatment in Children with Nephropathic Cystinosis. Long-term treatment with growth hormone in short children with nephropathic cystinosis. J Pediatr 2001 138(6) 880-7. 

Cystinosis can be produced experimentally in dogs by administration of 0.60 to 0.75 g of cystine per kilogram, and this produces a generalized hyperamino aciduria as well as albuminuria and finally mellituria in the premortal stage of the intoxication (S27, S29). This experimental cystinosis is attributed to a toxic effect of cystine at first on the renal functions and ultimately also on other tissues (S28, S30). From the genetic point of view, little is known. Some researchers believe cystinosis to be related to cystinuria (Al, H14, H16, P7). 

Excretion of cystine in abnormal amounts can occur in many other cases for instance in cystinosis, the characteristic feature of which is the deposit of cystine crystals in the body tissues, although cystinosis is not always accompanied by excessive excretion of cystine alone in the urine. In de Toni-Debre-Fanconi syndrome there is also an increased cystine output, but this is part of a generalized hyperamino aciduria such as... 

D20. Dern, P. L., Aminoaciduria with cystinosis case report with determination of urinary aminoacids and ocular cystine. Ann. Internal Med. 46, 138-144 (1957). 

F18. Freudenberg, E., Cystinosis, Cystine disease (Lignac s disease) in children. Advances in Pediat. 4, 265-292 (1949). 

K5. King, F. P., and Lochridge, E. P., Cystinosis (Cystine-storage disease) report of a case with biochemical isolation and quantitative determination of cystine in lymphnodes, spleen and liver. Am. J. Diseases Children 82, 446-455 (1951). 

W8. Weber, H., Beitrag zur Frage der Nierenfunktionsstorung bei Cystinosis. Helv. Paediat. Acta 8, 348-366 (1953). 

Autosomal recessive cystinosis is caused by an enzyme-induced blockage of cystine degradation, particularly in the RES lysosomes of the bone marrow, liver, spleen and kidneys. Especially in the stellate cells of the spleen and to a lesser extent of the hepatic lobule centres, hexagonal and rectangular cystine crystals are found, pointing at an early stage to cystinosis. There is evidence of hepatosplenomegaly and microvesicular steatosis. The clinical picture of the infantile type presents as a Fan-coni syndrome, (s. pp 593, 597) The children affected die in the first five years of life. 

Acute intermittent porphyria Atransferrinaemia syndrome Cystinosis... 

Mercaptamine is available for oral administration as hydrochloride and bitartrate salts and as sodium phosphomercaptamine. Topical mercaptamine prepared from the oral formulation has been used to treat severe photophobia from corneal crystal deposition in cystinosis (2). 

An 8-year-old boy with nephropathic cystinosis had debilitating and worsening photophobia from corneal crystal deposition (3). After 8 months of topical application of mercaptamine, he has marked improvement, both subjectively and objectively. 

In 93 children with nephropathic cystinosis oral mercaptamine 51 mg/kg for up to 73 months produced 82% cystine depletion from leukocytes and improved creatinine clearance and growth (8). However, 14% of the patients could not tolerate the taste and smell of mercaptamine, which is excreted in the breath. 

In four children with nephropathic cystinosis receiving mercaptamine 14.35 mg/kg qds serum gastrin concentrations up to 90 minutes later rose as did gastric acid output (10). Two of the four subjects had visual and histological evidence of gastric inflammation. The clinical effect of this acid production is unknown. 

Gahl WA. Early oral cysteamine therapy for nephropathic cystinosis. Eur J Pediatr 2003 162(Suppl 1) S38-41. 

Tsilou ET, Thompson D, Lindblad AS, Reed GF, Rubin B, Gahl W, Thoene J, Del Monte M, Schneider JA, Granet DB, Kaiser-Kupfer MI. A multicentre randomised double masked clinical trial of a new formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis. Br J Ophthalmol 2003 87(1) 28-31. 

Khan AO, Latimer B. Successful use of topical cysteamine formulated from the oral preparation in a child with keratopathy secondary to cystinosis. Am J Ophthalmol 2004 138 (4) 674-5. 

Corden BJ, Schulman JD, Schneider JA, Thoene JG. Adverse reactions to oral cysteamine use in nephropathic cystinosis. Dev Pharmacol Ther 1981 3(l) 25-30. 

Gahl WA, Ingelfinger J, Mohan P, Bernardini I, Hyman PE, Tangerman A. Intravenous cysteamine therapy for nephropathic cystinosis. Pediatr Res 1995 38(4) 579-84. 

Gahl WA, Reed GF, Thoene JG, Schulman JD, Rizzo WB, Jonas AJ, Denman DW, Schlesselman JJ, Corden BJ, Schneider JA. Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med 1987 316(16) 971-7. 

Wenner WJ, Murphy JL. The effects of cysteamine on the upper gastrointestinal tract of children with cystinosis. Pediatr Nephrol 1997 ll(5) 600-3. 

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