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A two-year-old boy with nephropathic cystinosis was successfully treated with cysteamine eye drops. Using topical cysteamine 0.1% every two hours in the right eye we found a clearance of crystals from the cornea after 26 weeks. In the left eye, treated with topical cysteamine 0.5% the same result was reached after 12 weeks.
We studied the effects of cysteamine in five children with nephropathic cystinosis who were treated for up to 30 months. Cysteamine caused a decline in leukocyte cystine levels to the range seen in clinically unaffected heterozygotes; both plasma and urinary cystine diminished by more than half. Therapy had no effect on progressively declining creatinine clearance in three patients, but improvement occurred in the other two. Phosphaturia, glycosuria, aminociduria, and organic aciduria did not improve in any of the patients. Both blood lactate and the lactate pyruvate ratio were diminished. Growth velocity, which was abnormal in four of the five children, did not improve. No major side effects were noted. Therapy with cysteamine caused a consistent, dose-related decline in levels of cystine in leukocytes and in extracellular fluid, caused no improvement so far in renal tubular function or growth velocity, and improved creatinine clearance in some patients.
The metabolism of amino acids, peptides, and disulfides has been investigates in cultured skin fibroblasts from normal individuals and patients with cystinosis. Human fibroblast lysosomes closely resemble the lysosomes of mouse peritoneal macrophages in having an apparent permeability barrier to amino acids and peptides with molecular weights of greater than 220-230. Cystinotic and normal cells behave similarly in this regard. Normal cells do not undergo lysosomal swelling when exposed to cysteine-penicillamine disulfides, while cystinotic cells are prominently vacuolized under these conditions. Normal lysosomes may have a specific mechanism for the disposal of cystine, and deficient activity of this mechanism in cystinotic lysosomes could result in cystine storage therein. The demonstration that human fibroblasts can be used conveniently to study lysosomal metabolism of small substrates may facilitate investigations of these aspects of lysosomal function in a variety of genetic diseases of man.
The eldest autopsied case (a 23-year-old man) of infantile form of cystinosis with uremia and myxoedema was reported. The cystine content per gram wet tissue of various organs was arranged as follows: the thyroid (4.61 mg), kidney (1.71 mg), eye (0.75 mg), spleen (0.65 mg), liver (0.49 mg), and brain (0.016 mg). In polarized light microscopy, cystine crystals were detected in the epithelial cells and epithelial lumina of both kidneys by Wollaston test, and foam cells with cystine crystals were histologically found in the reticuloendothelial and other organs, especially in the bone marrows. Moreover, electron microscopic findings revealed square, rectangular or lozenge-shaped small cystine crystal profiles in osmophilic dense bodies of the histiocytic cells and in the cytoplasm of the foam cells. In some of them, positive reaction for acid phosphatase activity was specifically localized at the periphery of the cystine crystal profiles.
We report a case of 6 year old girl with Fanconi syndrome the origin of which was suspected to be cystinosis. Pathological findings of a renal biopsy showed needle-like materials in the epithelial cells but the cystine content of the white blood cells was normal. Although excessive urinary loss of growth hormone was detected, the height and weight of the patient was normal. Urinary loss of growth hormone did not cause growth retardation in this case.
Cystinosis is an autosomal recessive disease that results in a defective integral membrane protein responsible for the transport of cystine out of lysosomes. This results in the accumulation of cystine in the lysosomes of almost every tissue, with subsequent formation of damaging crystals. The cystinotic process may affect every system of the body, but is particularly damaging to the kidneys and eyes. We discuss the perioperative care of a cystinotic patient with renal insufficiency, Fanconi's syndrome, and photophobia. Other organ systems affected by the cystinotic process are also discussed, with suggestions for the perioperative management of each. Issues of primary concern during perioperative care include preservation of renal function and maintenance of fluid and electrolyte homeostasis.
A simple method for the biochemical diagnosis of cystinosis involves incubating leukocytes from a small volume of blood with 35S-cystine. Non-protein 35S-labelled compounds are then extracted from the leucocytes and separated by thin-layer chromatography. The excessive incorporation of 35S-cystine into the increased cystine pool of cystine cells is easily detected in autoradiographs of the chromatograms.
The psychosocial and intellectual development of 12 children with infantile nephropathic cystinosis was investigated longitudinally by use of biographical data, long-term behavioral observations and psychological assessment. Of the 12 patients, eleven suffered terminal renal failure and 7 of these were followed up after renal transplantation. In spite of the severe illness and the resulting unusual life conditions the patients showed normal intellectual capacity and most of them average school performance. The patients were socially adapted, their behavior was predominantly cooperative, shy and reserved, but depressive at times. After transplantation the children became more active and outgoing. However, growing discrepancies between their physical development and their emotional and social age may lead to adaptational problems at adolescence which may require psychological counselling.
In patients with cystinosis, the concentration of free cystine in leukocytes was 80 times greater than normal, and six times the normal content for their parents. This is the first demonstration of an abnormality in heterozygotes for this rare inherited disease of childhood. Three-quarters of the cystine was recovered in the granular fraction of cystinotic leukocytes.
In cultured fibroblasts from individuals with cystinosis vacuolation is induced by exposure to L-cysteine-D-penicillamine disulfide. Normal fibroblasts do not show vacuolation on such exposure. These observations provide direct evidence that cystinotic cells have deficient activity of a lysosomal system for disulfide metabolism or transport. Induction of vacuolation by the mixed disulfide in cystinotic but not in normal cells furnishes a histological marker for cystinotic fibroblasts.
We describe a patient with early diagnosed cystinosis who presented with nephrogenic diabetes insipidus in addition to proximal tubular dysfunction. Another feature in this patient was abnormally low serum concentration of 24,25 dihydroxy vitamin D3 (24,25(OH)2D3) with normal 25 hydroxy vitamin D3 (25(OH)D3) and relatively low 1,25 dihydroxy vitamin D3 (1,25(OH)2D3).
Diurnal variation in leucocyte cystine and the effects of equimolar single doses of oral phosphocysteamine and rectal cysteamine were studied in eight patients with cystinosis, aged 1.8-16.5 years. No significant diurnal variation in leucocyte cystine was found. Absorption of cysteamine was reduced after rectal administration compared with the oral dose: mean (SD) peak concentration 17.2 (6.3) mumol/l v 36.4 (5.5) mumol/l at 40 min and mean (SD) area under the curve 22.3 (14.3) v 59.4 (33.1) mumol/h/l. Oral phosphocysteamine significantly reduced the mean (SD) leucocyte cystine from 8.09 (0.47) to 3.26 (1.48) nmol 1/2 cystine/mg protein at three hours. At 12 hours the mean leucocyte cystine was significantly lower than the pretreatment concentration. Rectal cysteamine did not significantly reduce the mean leucocyte cystine concentration. In conclusion, phosphocysteamine suspension may be administered every 12 hours. Rectal cysteamine administration is feasible but higher doses are required before efficacy can be judged.
A 2-year-old girl with nephropathic cystinosis was successfully treated with topical cysteamine 0.5% to one eye. Clearance of crystals from the treated cornea was virtually complete after three months. The possibilities and limitations of this form of treatment are discussed.
AIM: To evaluate the safety and efficacy of a new topical cysteamine formulation, stable at room temperature, for the treatment of corneal cystine crystals in cystinosis. METHODS: 20 study subjects were enrolled in the safety study and 16 in the efficacy study. Both studies were randomised and double blind. The primary outcome for the safety study was the occurrence of predefined serious adverse reactions over 6 months and for the efficacy study the reduction of corneal cystine crystal score (CCCS) by 1.00 or more units on photographs graded by a reading centre using a standardised protocol. RESULTS: No study subject developed any serious adverse reactions. In the efficacy study, 47% of eyes receiving the standard formulation experienced a reduction in the CCCS of >/=1.00 after 1 year, while 7% of eyes on the new formulation experienced such a decrease (p=0.04). CONCLUSION: Although no serious adverse reactions were observed with either formulation, the new formulation was not as effective as the standard formulation.
AIM: To investigate the morphology and function of platelets in nephropathic cystinosis (NC). METHODS: Seven patients (mean age, 6.5 years; SD, 20 months) with NC were investigated. Their platelets were examined by transmission electron microscopy (TEM) and the characteristics of the dense granules (DGs) were determined by mepacrine labelling and the uranaffin reaction. Bleeding time, turbidometric aggregation, and luminescence aggregation were studied and intraplatelet cystine was measured. RESULTS: Increased intraplatelet cystine, primary and secondary aggregation defects, and the absence of ATP release were demonstrated. TEM revealed DGs of various shapes and sizes and lamellary or amorphous cytoplasmic inclusions. Viscous material had been released into the vacuolar spaces and enlarged open canalicular system. Mepacrine labelling revealed that the numbers of DGs/platelet were comparable between the patients and the controls (mean, 2.9 (SD, 0.22) v 3.32 (0.18); p = 0.34). The uranaffin reaction revealed that the numbers of type 1, 3, and 4 DGs were comparable between the patients and the controls, but that there were fewer type 2 DGs in the patients (mean, 8.5 (SD, 1.95) v 17.22 (1.58); p = 0.01). TEM for platelet aggregation revealed a lack of induction and/or defective execution and/or delayed transmission. The patients' intraplatelet cystine concentrations were higher than the controls (mean, 1.56 (SD, 0.84) v 0.08 (0.01) nmol/mg protein; p = 0.009). CONCLUSIONS: This is the first report to demonstrate raised intraplatelet cystine, abnormal platelet ultrastructural findings, and defective aggregation in NC.
Infantile nephropathic cystinosis, an inborn error of metabolism with an autosomal recessive inheritance pattern, is characterized by lysosomal storage of the amino acid cystine due to an impaired transport of cystine out of the lysosomes. Initial clinical features consist of the renal Fanconi syndrome and crystals in the cornea. Oral therapy with cysteamine lowers the intracellular cystine content. Recently, the gene coding for the integral membrane protein cystinosin, which is responsible for membrane transport of cystine (CTNS), was cloned. Mutation analysis of the CTNS gene of Caucasian patients revealed a common 57-kb deletion, and several other mutations spread throughout the entire gene. In the present study, we developed an improved screening method for the detection of the common 57-kb deletion. By use of this method we detected the 57-kb deletion in 59% of the examined Dutch alleles. The remaining alleles were screened for other mutations by genomic sequencing of the different exons, revealing three previously described mutations. Furthermore, we studied a possible genotype-phenotype relation of the homozygous deleted patients, which could not be demonstrated in our study population. Next to biochemical determination of cystine in leukocytes or fibroblasts, molecular genetic analysis enables prenatal diagnosis and facilitates identification of carriers.
Three phenotypic forms of cystinosis (nephropathic, juvenile-onset and benign adult forms) are well recognized. That not all infants and children have the classical nephropathic form with Fanconi's syndrome is illustrated by 2 of the 3 patients in this report. Case 1 had the typical nephropathic form with generalized proximal tubular dysfunction. In contrast, case 2 had transient features of Bartter's syndrome which preceded the manifestations of Fanconi's syndrome. Case 3 was more complex because he first presented with a syndrome of nephrogenic diabetes insipidus. He then developed features of Fanconi's syndrome as well as metabolic acidosis, hyponatremia and hyperkalemia. The failure of deoxycorticosteroid administration to elevate the serum concentration suggested, in retrospect, that he may also have had a form of acquired pseudohypoaldosteronism.
The purpose of this study was to examine the effect of hypotonic saline diuresis on two patients with cystinosis, trying to localize the site of renal sodium loss. At the same time, we have performed the same hypotonic saline infusion under hydrochlorothiazide administration. Results seem to prove the proximal tubular localization of the salt-wasting syndrome in cystinotic patients. On the other hand, these results suggest that hydrochlorothiazide effect can be related to the hypovolemia due to the distal tubular action of hydrochlorothiazide that could inhibit the 'third' natriuretic factor, thus increasing the proximal tubular sodium reabsorption.