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PubMed1983

[Retinal changes in cystinosis].

Cystinosis is a rare autosomal recessive hereditary enzymopathy which leads to accumulation of cystine in the reticuloendothelial system of the liver, spleen, lymph nodes, etc. The pathognomonic alterations of the cornea are characterized by multiple crystalline deposits, chiefly in the limbus area and in the anterior corneal stroma. The retinal changes are seldom described in the literature; they are characterized by a fine-grained pigment shift which intensifies from the macula toward the preequator area and which gives the fundus a 'salt and pepper' appearance.

Adolescent↗
PubMed1987

Disorders of lysosomal membrane transport--cystinosis and Salla disease.

Two lysosomal storage diseases are now known to result from impaired transport of small molecules across the lysosomal membrane. In cystinosis, the disulfide amino acid, cystine, accumulates and in free sialic acid storage disorders, N-acetylneuraminic acid is stored. The lysosomal cystine carrier exhibits saturability, counter-transport, temperature dependence, and stereospecificity; it is highly specific for molecules resembling cystine. Less is known about sialic acid transport, but its temperature dependence and deficiency in certain autosomal-recessive human mutations strongly suggests that it is a carrier-mediated process. Cystine and sialic acid serve as prototypes for amino acids and sugars transported by specific lysosomal membrane carriers, whose impairment results in lysosomal storage disorders.

Cystinosis↗
PubMed1968

An experimental renal acidification defect in patients with hereditary fructose intolerance. II. Its distinction from classic renal tubular acidosis; its resemblance to the renal acidification defect associated with the Fanconi syndrome of children with cystinosis.

In adult patients with hereditary fructose intolerance (HFI) fructose induces a renal acidification defect characterized by (a) a 20-30% reduction in tubular reabsorption of bicarbonate (T HCO(3) (-)) at plasma bicarbonate concentrations ranging from 21-31 mEq/liter, (b) a maximal tubular reabsorption of bicarbonate (Tm HCO(3) (-)) of approximately 1.9 mEq/100 ml of glomerular filtrate, (c) disappearance of bicarbonaturia at plasma bicarbonate concentrations less than 15 mEq/liter, and (d) during moderately severe degrees of acidosis, a sustained capacity to maintain urinary pH at normal minima and to excrete acid at normal rates. In physiologic distinction from this defect, the renal acidification defect of patients with classic renal tubular acidosis is characterized by (a) just less than complete tubular reabsorption of bicarbonate at plasma bicarbonate concentrations of 26 mEq/liter or less, (b) a normal Tm HCO(3) (-) of approximately 2.8 mEq/100 ml of glomerular filtrate, and (c) during acidosis of an even severe degree, a quantitatively trivial bicarbonaturia, as well as (d) a urinary pH of greater than 6. That the fructose-induced renal acidification defect involves a reduced H(+) secretory capacity of the proximal nephron is supported by the magnitude of the reduction in T HCO(3) (-) (20-30%) and the simultaneous occurrence and the persistence throughout administration of fructose of impaired tubular reabsorption of phosphate, alpha amino nitrogen and uric acid.A reduced H(+) secretory capacity of the proximal nephron also appears operative in two unrelated children with hyperchloremic acidosis, Fanconi's syndrome, and cystinosis. In both, T HCO(3) (-) was reduced 20-30% at plasma bicarbonate concentrations ranging from 20-30 mEq/liter. The bicarbonaturia disappeared at plasma bicarbonate concentrations ranging from 15-18 mEq/liter, and during moderate degrees of acidosis, urinary pH decreased to less than 6, and the excretion rate of acid was normal.

Acid-Base Equilibrium↗
PubMed1976

Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo.

Certain aminothiols rapidly deplete cultured cystinotic skin fibroblasts of their abnormally high free (nonprotein) cystine pool. The free cystine content of these cells if reduced by over 90% in 1 h with 0.1 mM cysteamine. This is more rapid than previously known methods of removing free cystine from cystinotic fibroblasts. The disulfide, cystamine, is also able to deplete cystinotic cells of free cystine. A patient with nephropathic cystinosis and end-stage renal disease was treated with cysteamine, both intravenously and orally. Both methods of administration rapidly lowered the free cystine content of the patient's peripheral leukocytes. Study of the patient's urinary sulfur excretion did not conclusively determine the effect of this therapy on the total body cystine pool. Her renal status remained at end stage after 1 mo of oral cysteamine, when an episode of grand mal seizures prompted cessation of the study. Determination of the proper place of aminothiol therapy in this disease will depend upon further clinical trial with patients whose kidney function has not deteriorated to the point of irreversible change, accompanied by careful monitoring of plasma aminothiol levels.

Child↗
PubMed1995

Intravenous cysteamine therapy for nephropathic cystinosis.

A 4-y-old boy with nephropathic cystinosis and gastrointestinal dysmotility of unknown etiology was treated with i.v. cysteamine over a period of 10 mo. Thirty minutes after a dose of 10 mg/kg cysteamine free base, the leukocyte cystine value had fallen from 11.9 to 4.9 nmol of half-cystine/mg of protein. When cysteamine was given every 6 h, the leukocyte cystine concentration, measured 5-7 h after a dose, decreased with increasing cysteamine doses up to 17 mg/kg; at this dose the cystine value was 1.1 nmol of half-cystine/mg of protein, or 9% of the untreated value. Oral administration of approximately 16 mg/kg per dose every 6 h to this patient over the previous 3 y achieved similar leukocyte cystine depletion, to 1.2 nmol of half-cystine/mg of protein. The plasma cysteamine concentration 30 min after a dose of 10 mg/kg was 71 microM; 5-7 h after a dose of up to 20 mg/kg, the concentration was below 5 microM. Dimethylsulfide was elevated in the breath and urine of this boy after, but not before, the initiation of i.v. cysteamine therapy. Ten months after the start of therapy, the patient tolerated 250 mg (14 mg/kg) every 8 h. Adverse effects of this treatment included lethargy and increased nausea and vomiting when a schedule of therapy every 6 h was attempted. This investigation demonstrates that cysteamine given through a central venous catheter is effective in reducing leukocyte cystine levels.

Child, Preschool↗
PubMed2006

Impaired activity of the gamma-glutamyl cycle in nephropathic cystinosis fibroblasts.

Cystinotic patients have been shown to excrete in their urine high levels of pyroglutamate, an intermediate metabolite of the adenosine triphosphate (ATP)-dependent gamma-glutamyl cycle, which is responsible for glutathione (GSH) synthesis. Human fibroblasts were used to study the mechanisms leading to pyroglutamate accumulation in nephropathic cystinosis (NC). We show that inhibition of ATP synthesis caused a marked intracellular accumulation of pyroglutamate, reflecting decreased GSH synthesis. Despite similar degrees of ATP depletion, pyroglutamate increased more in cystinotic fibroblasts than in controls, while GSH decreased to lower levels. In addition, cystinotic cells exposed to oxidative stress (hydrogen peroxide) were unable to increase their GSH concentration above baseline. These results could not be attributed to differences in mitochondrial oxidative activity or to increased apoptotic cell death. Together, these results support the hypothesis that cysteine derived from lysosomal cystine efflux limits the activity of the gamma-glutamyl cycle and GSH synthesis.

Adenosine Triphosphate↗
PubMed1982

Nonabsorptive hydrocephalus associated with nephropathic cystinosis.

A child with nephropathic cystinosis developed seizures and coma. CT showed prominent sulci and slight ventricular enlargement. Nuclear cisternogram was normal. Despite successful renal transplantation and treatment of hypothyroidism, neurologic recovery was poor. CT and nuclear cisternogram 5 months later showed moderate panventricular and subarachnoid space enlargement and abnormal ventricular isotope retention. Ventriculoperitoneal shunt placement was followed by improved intellectual function, resolution of pyramidal tract signs, and control of seizures. Anisotropic crystals consistent with cystine were demonstrated in biopsy samples of arachnoid and cerebral cortex. Nonabsorptive hydrocephalus may have resulted from deposition of cystine in the meninges.

Arachnoid↗
PubMedDate not supplied

Renal cells in culture as a model for cystinosis.

The established renal cell line LLC-PK1 was used as a model to investigate the mechanism underlying kidney malfunction observed in cystinosis patients. In this disease lysosomal accumulation of cystine impairs kidney function, and glycosuria is an early clinical manifestation. The linkage between lysosomal accumulation of cystine and impairment of kidney function is still unclear, and no animal model is available. In an attempt to gain a better insight into this relationship, we studied the effects of lysosomal loading with cystine on the survival and functions of normal noncystinotic renal epithelial cells (LLC-PK1), nonrenal fibroblasts (NIH-3T3), and cystinotic fibroblasts (GM2837). Incubation of the cells with cystine dimethylester (CDME) resulted in time- and dose-dependent accumulation of cystine, with 80% of the cystine in the lysosomal fraction. The lysosomal concentration of cystine increased in the three cell lines after 3 hours of incubation and declined significantly after 48 hours in the normal, but not cystinotic, cells. The accumulation of cystine in the lysosomes caused dose- and time-dependent cell mortality, assessed by measuring the activity of the cytosolic enzyme, lactic dehydrogenase, in the medium. Survival of fibroblasts and renal cells was similar in all three cell lines. The concentrating capacity (the ratio fo the intra- and extracellular concentrations) of the nonmetabolized sugar analog, alpha methyl glucoside (AMG), was used to assess the function of the kidney cells. The sugar concentrating capacity of LLC-PK1 cells was reduced after incubation with CDME in a dose- and time-dependent manner. Since there was no change in sugar efflux between the untreated and treated cells, we conclude that an impairment of the uptake of AMG is responsible for the reduction in the sugar-concentrating capacity in LLC-PK1 cells. In the absence of a genetically impaired animal model, LLC-PK1 cells treated with CDME can be used to investigate the cellular mechanisms responsible for the impairment of kidney function in cystinotic patients.

Alanine↗
PubMed1997

Nephropathic cystinosis.

Nephropathic cystinosis is one of the only lysosomal storage diseases for which there is an effective therapy against the basic, pathologic process-cystine accumulation. Early diagnosis and therapy are critical to optimize the prognosis.

Acidosis, Renal Tubular↗
PubMed1977

Hypothyroidism in cystinosis.

It has recently been shown that hypothyroidism complicates cystinosis. The radiographic bone changes of hypothyroidism (retarded skeletal age) cannot be detected while the patient has overt rickets, since the secondary ossification centers are not ossified. When the rickets is treated and the secondary ossification centers fail to appear (the skeletal age remains retarded), then the diagnosis of hypothyroidism should be suspected. After treatment with thyroid hormone is begun and a growth spurt occurs, rickets that has been controlled may reactivate. The previous doses of vitamin D will no longer be adequate because of the patient's growth spurt.

Child↗
PubMedDate not supplied

Long-term ocular changes in cystinosis: observations in renal transplant recipients.

Following renal transplantation in nephropathic cystinosis, an extension of retinopathy associated with a variety of subtle functional ocular abnormalities may occur. However, these abnormalities have not (except for photophobia) been of subjective significance to cystinotic patients. Our data, gathered from patients transplanted as long as nine years ago, indicate that cystinotic patients should not have renal transplant withheld because of the fear of subsequent progressive ocular deterioration.

Adolescent↗
PubMedDate not supplied

The effect of topical cysteamine drops on reducing crystal formation within the cornea of patients affected by nephropathic cystinosis.

We studied the usefulness of topical cysteamine ophthalmic drops in reducing crystal formation within the corneas of patients affected by nephropathic cystinosis. A dosage of 0.3% cysteamine given four times daily was chosen as a more manageable method than a previously reported protocol of hourly administration of 0.11% drops. No reduction in crystal formation was observed in our patients; they were followed for seven months.

Administration, Topical↗
PubMed1976

Glomerulonephritis in late-onset cystinosis. Report of two cases and review of the literature.

This paper describes the clinical history of two male nontwin siblings with late-onset cystinosis, a variant of cystine storage disease. The diagnosis was established clinically and confirmed by measurement of cystine concentrations in leucocytes and skin-fibroblasts. Both patients presented with an incomplete nephrotic syndrome and renal biopsy showed, in addition to lesions of polykaryocytosis, a picture of focal and segmental glomerular hyalinosis. Renal function was stable in one patient over a follow-up period of two years; the other patient progressed toward terminal renal failure and was successfully transplanted.

Adolescent↗
PubMed1999

Neurophysiological testing in long-standing cystinosis.

Neurophysiological data of two brothers with long-standing cystinosis are presented. Both patients showed a distally symmetrical myopathy affecting the arms more than the legs. Myopathy occurred before the onset of polyneuropathy or signs of central nervous involvement.

Adult↗
PubMed1999

Cysteamine: new preparation. Chronic treatment of cystinosis.

(1) Cysteamine bitartrate (also known as mercaptamine) is marketed for the treatment of cystinosis, a rare hereditary disease which, in its juvenile and infantile forms, progresses spontaneously to severe renal and ocular impairment, growth retardation with rickets, and involvement of many other organs. Only symptomatic treatments have been available until now. (2) The clinical file includes only non comparative trials. (3) Few children have been treated with cysteamine beyond the age of 10. Provided treatment is begun early, the main beneficial effects of cysteamine are maintenance of the growth curve and prevention of deterioration of renal lesions (an effect that varies from patient to patient). Oral cysteamine does not prevent the progression of ocular lesions. (4) Cysteamine has many potential adverse effects, some of which are serious (mainly gastrointestinal and neuropsychiatric disorders). Little is known of its long-term adverse effects. (5) The main disadvantage of this treatment is the need for four daily intakes (every 6 hours) and the sulphurous breath it causes. (6) Treatment with cysteamine is expensive.

Adolescent↗
PubMedDate not supplied

The Fanconi syndrome of cystinosis: insights into the pathophysiology.

Cystinosis is a lysosomal storage disease, and is one of the most common causes of the Fanconi syndrome. In vitro studies of the cystine-loaded tubule provided insights into the pathophysiology of the proximal tubular defect. Proximal tubules loaded with cystine have a generalized proximal tubule transport defect characteristic of the Fanconi syndrome. The decrease in proximal tubular transport with cystine loading is due to a decrease in active transport. In cystine-loaded tubules the ATP production is severely compromised. The cystine-loaded tubule has a lower intracellular phosphate concentration than that of control tubules. This low intracellular phosphate concentration in cystine-loaded tubules likely plays an important role in maintaining intracellular ATP level. Preservation of intracellular phosphate at control levels prevents the decrease in intracellula, ATP and the proximal tubule respiratory dysfunction with cystine loading.

Cystinosis↗
PubMed2003

Infantile cystinosis.

Ten patients of nephropathic cystinosis were admitted during the period 1995-2000. Their mean age was 12 months. The signs of failure to thrive and advanced rickets were seen in all patients. Other features included polyuria, polydipsia, pathologic fractures and deafness. Laboratory findings included glucosuria, hyposthenuria, hypocalcemia, proteinuria and azotemia. Therapy with phosphocysteamine showed marked clinical improvement.

Acidosis, Renal Tubular↗