Biochemical Comparisons of the Adult and Childhood Forms of Cystinosis

Ja, Schneider; Wong, K.F.; Bradley, Kathryn H.; Je, Seegmiller

doi:10.1056/nejm196812052792303

Cited by 67 publications

(14 citation statements)

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“…This has been demonstrated previously for cystinotic fibroblasts in culture [37,38]. The cystine levels in the cultured CC were somewhat lower than the levels found in the fibroblasts [37] or in peripheral CC (uncultured) [35].…”

Section: Discussionsupporting

confidence: 80%

“…Cystinotic tissues contain large excesses of cystine, which are often visible in appropriately prepared tissues as intracellular crystalline deposits. Cystinotic white cells [35] and cultured fibroblasts [37,38] contain increased intracellular cystine levels, and the metabolic defect responsible for cystinosis, which has so far eluded delineation, may be investigated in these cells. Considerable evidence suggests that cystinosis is a lysosomal storage disease [21, 30, 39-41, 43, 50].…”

Section: Introductionmentioning

confidence: 99%

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Biochemical, Morphologic, and Gytogenetic Studies of Leukocytes Growing in Continuous Culture from Normal Individuals and from Patients with Cystinosis

et al. 1971

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Continuous leukocyte cultures were established from the blood of three siblings with classical nephropathic cystinosis and from their mother. The cells from patients with cystinosis (CC) contained at least 15-to 20-fold more cystine than cultured leukocytes from normal individuals (NC). The transport of cystine-35 S into CC was similar to uptake into NC when tested at pH 5.0 and pH 7.4.The cultured CC could not be distinguished by ultrastructure from NC Crystalline inclusions which could easily have been mistaken for cystine were observed in the lysosome of a normal cell. The modal number of chromosomes in CC and NC lines was 46. There was a marked degree of aneuploidy. Tetraploidy was present in 3.8-9.6% of metaphases. Structural rearrangements and breaks were seen in all cell lines. Speculation

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Biochemical, Morphologic, and Gytogenetic Studies of Leukocytes Growing in Continuous Culture from Normal Individuals and from Patients with Cystinosis

et al. 1971

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“…Investigators have attempted to explain why these patients, who have accumulations of cystine crystals in many of the same tissues as patients with nephropathic cystinosis, do not have renal damage. The first biochemical difference noted in patients with benign cystinosis was that the cystine content of their leukocytes, although elevated, was not elevated to the same range as in patients with infantile nephropathic cystinosis (8,26). Kidney biopsy samples from two patients with benign cystinosis demonstrated no cystine crystals (24,29), and the cystine content of the one biopsy sample measured was not elevated (29).…”

Section: Discussionmentioning

confidence: 99%

“…Since Cogan et al described the first case of benign cystinosis in 1957, many other cases have been reported (23)(24)(25)(26)(27)(28)(29)(30). Investigators have attempted to explain why these patients, who have accumulations of cystine crystals in many of the same tissues as patients with nephropathic cystinosis, do not have renal damage.…”

Section: Discussionmentioning

confidence: 99%

Lack of complementation in somatic cell hybrids between fibroblasts from patients with different forms of cystinosis.

Pellett

Smith

Greene

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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Cystinosis is an autosomal recessive disease in which three clinical forms are recognized: infantile nephropathic, with renal tubular damage by 1 year of age and progressive glomerular insufficiency; intermediate, with tubular and glomerular insufficiency beginning at a later age; benign, with no kidney damage. Skin fibroblasts cultured from patients with all types of cystinosis show increased intralysosomal free (nonprotein) cystine; however, fibroblasts from heterozygotes have normal free-cystine values. To determine whether genetic complementation occurs between the different forms, somatic cell hybrids were constructed between cells from a patient with infantile nephropathic cystinosis and cells from patients with other types ofcystinosis. Ifcomplementation occurred, the hybrids would be expected to have normal cystine levels. To construct hybrid cells, a "universal parent" cell type (TG1-neo), which was hypoxanthine/aminopterin/thymidine (HAT) sensitive and G418 resistant was constructed from an infantile nephropathic cystinosis fibroblast strain. Polyethylene glycol fusion of TG1-neo with other cells that are not HAT sensitive or G418 resistant allowed for selection of hybrid cells in a medium containing HAT and the aminoglycoside G418. As indicated by elevated cystine levels, complementation did not occur between TG1-neo and two different benign cystinosis strains, an intermediate cystinosis strain, or another nephropathic cystinosis cell strain. When a normal fibroblast strain was fused with TG1-neo, all 15 hybrid clones studied contained normal amounts of intracellular free cystine.

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“…This may be relevant to the biochemical pathology of the three conditions. Cystinosis is thought not to result from a block in cystine metabolism but to be due to lysosomal accumulation of the amino acid (19). The P cell fraction in the cases of cystinosis was skewed above the 50th centile.…”

Section: Discussionmentioning

confidence: 99%

The Pancreatic β Cell Fraction in Children with Errors of Amino Acid Metabolism

Milner

Wirdnam

1982

Pediatr Res

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Summarylected by searching the archives from 1960 to 1978 of the histoBlocks of pancreas were obtained from the following cases of errors of amino acid metabolism: eight cystinosis, eight tyrosinosis, five phenylketonuria, three hypermethioninemia, two hyperprolinemia and two maple syrup urine disease. Blocks were also obtained from four cases of homocystinuria and 72 control patients of the same age range who had died from a variety of conditions believed not to affect the pancreas. Sections were cut from each pancreatic block and stained with haematoxylin or for insulin and pancreatic polypeptide (PP) by the immunoperoxidase method. Measurements were performed separately in the P P rich and the P P poor regions of all sections. The fractional surface area of section occupied by insulin stained cells (%) and the cellular density (nuclei/100 pm2) of each specimen were estimated. The p cell fractional area in the P P poor region of the experimental cases was plotted against the logarithm of gestational age and compared to a reference grid of the loth, 50th and 90th centile estimates of the control cases (Fig. 1). The distribution of results from the cases of tyrosinosis, phenylketonuria and cystinosis were skewed positively; four of eight tyrosinosis and three of five phenylketonuria cases lying above the 90th centile ( P < 0.001).The fl cell fractional area of the cystinosis cases was also significantly increased (Table 1, P < 0.05). The results from the cases dying from maple syrup urine disease, hyperproliemia, hypermethioninemia or homocystinuria were distributed as might be expected to occur by chance. SpeculationThe abnormal metabolic environment that occurs in some inborn errors of amino acid metabolism may lead to pancreatic j3 cell hyperplasia. The increased j3 cell mass found in tyrosinosis, cystinosis and phenylketonuria, if accompanied by hyperinsulinism, may be responsible for hypoglycemia.Patients suffering from untreated inborn errors of amino acid metabolism may have a generalized or a selective hyperaminoacidemia. Tyrosinosis is not a clear cut example of an inborn metabolic error (3, 4) but some patients with type I tyrosinemia have been reported to exhibit hypoglycemia and, at necropsy, to have pancreatic islet hyperplasia (4, 15). Our interest in a systematic study of , 8 cell development in children dying from errors of amino acid metabolism was prompted by the anecdotal description of type I tyrosinemia, the knowledge that amino acids are insulin secretogogues (5) and the discovery that amino acids could selectively stimulate / 3 cell growth and insulin accumulation by embryonic rat pancreas grown in vitro (6, 11). MATERIALS AND METHODSPancreatic specimens. Errors of amino acid metabolism are uncommon and specimens of pancreas from such patients who die and undergo necropsy are even more so. Pancreatic blocks from patients dying from errors of amino acid metabolism were colpatholoiy departGents of six hospitals:

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Biochemical Comparisons of the Adult and Childhood Forms of Cystinosis

Cited by 67 publications

References 14 publications

Biochemical, Morphologic, and Gytogenetic Studies of Leukocytes Growing in Continuous Culture from Normal Individuals and from Patients with Cystinosis

Biochemical, Morphologic, and Gytogenetic Studies of Leukocytes Growing in Continuous Culture from Normal Individuals and from Patients with Cystinosis

Lack of complementation in somatic cell hybrids between fibroblasts from patients with different forms of cystinosis.

The Pancreatic β Cell Fraction in Children with Errors of Amino Acid Metabolism

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