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PubMed1976

Infantile cystinosis in France: genetics, incidence, geographic distribution.

A national distribution of 66 French patients, from 49 sibships, has been studied. Segregation analysis, using the maximum likelihood method, was found to agree with the theoretical values expected in recessive autosomal inheritance. The birthplaces of these patients show an unequal geographic distribution of cystinosis, the incidence being higher in Western France. Compared with the total number of live births during the period 1959 to 1972, the minimum incidence of the condition in the province of Brittany is 1 per 25 909, and the gene frequency 0.0062. In the rest of France, the minimum incidence is 1 per 326,440 and the gene frequency 0.0018. Application of Dahlberg's formula gives a similar result. The mean inbreeding coefficient is 530 X 10(-5), a figure 23 times higher than the mean coefficient of France. An indirect test of inbreeding, the distance between parental birthplaces, was studied, first using the French administrative boundaries, second by using kilometers. This distance was constantly smaller for the parents of patients than for the parents of controls. Analysis of two erythrocyte polymorphisms (ABO and Rh) showed a large excess of group A patients when compared with overall French data. These findings are difficult to interpret on genetic grounds. The genetic reasons for the unequal geographic distribution of cystinosis in France are discussed.

ABO Blood-Group System↗

PubMed1981

Adverse reactions to oral cysteamine use in nephropathic cystinosis.

Cysteamine (2-aminoethanethiol) has been given orally to 19 patients with nephropathic cystinosis for periods of 8-24 months in doses ranging from 50 to 70 mg base/kg/day. Adverse reactions were noted in 3 patients early in the study when a rapidly increasing dosage schedule was followed. The reactions included hyperthermia, lethargy and rash. These reactions were not seen when patients were started on a very low dosage which was increased gradually at 3-week intervals to a level which depleted leukocytes of about 90% of their free cystine. All three reactions resolved within 24 h or cessation of therapy and in these cases successful readministration of drug was achieved. Chronic cysteamine administration to pediatric patients with cystinosis is feasible. The efficacy of this therapy is still being evaluated.

Child↗

PubMed1985

Metabolism of pantethine in cystinosis.

D-Pantethine is a conjugate of the vitamin pantothenic acid and the low-molecular-weight aminothiol cysteamine. Pantethine is an experimental hypolipemic agent and has been suggested as a source of cysteamine in the treatment of nephropathic cystinosis. We treated four cystinotic children with 70-1,000 mg/kg per d oral D-pantethine and studied its metabolism. Pantethine was rapidly hydrolyzed to pantothenic acid and cysteamine; we could not detect pantethine in plasma after oral administration. The responsible enzyme, "pantetheinase," was highly active in homogenates of small intestinal mucosa and plasma. The Michaelis constant of the rat intestinal enzyme was 4.6 microM and its pH profile showed a broad plateau between 4 and 9. Pantothenate pharmacokinetics after orally administered pantethine followed an open two-compartment model with slow vitamin elimination (t1/2 = 28 h). Peak plasma pantothenate occurred at 2.5 h and levels over 250 microM were seen at 300 times normal. Apparent total body storage of pantothenate was significant (25 mg/kg), and plasma levels were elevated threefold for months after pantethine therapy. Plasma cysteamine concentrations after pantethine were similar to those reported after equivalent doses of cysteamine. However, at best only 80% white blood cell cystine depletion occurred. We conclude that pantethine is probably less effective than cysteamine in the treatment of nephropathic cystinosis and should only be considered in cases of cysteamine intolerance. Serum cholesterol was decreased an average of 14%, which supports the potential clinical significance of pantethine as a hypolipemic agent. Rapid in vivo hydrolysis of pantethine suggests that pantothenate or cysteamine may be the effectors of its hypolipemic action.

Adolescent↗

PubMed2002

Nephropathic cystinosis associated with cardiomyopathy: a 27-year clinical follow-up.

BACKGROUND: Nephropathic cystinosis is an autosomal recessive disease resulting from intracellular accumulation of cystine leading to multiple organ failure. CASE REPORT: We describe the clinical course of a patient managed from the age of six until his death at the age of 33 years. He underwent multiple surgery, including two renal transplants, developed transplant renal artery stenosis that was managed medically, and progressive heart failure at the age of 33 years. His death from a ruptured pseudoaneurysm associated with a restrictive cardiomyopathy is noteworthy. A limited cardiac autopsy revealed the presence of cystine crystals in interstitial cardiac histiocytes and one myocardial cell, along with 1000-fold higher tissue cystine content of the left ventricular myocardium compared to patients without cystinosis, suggesting the possibility of direct cystine mediated metabolic injury.

Aneurysm, False↗

PubMed1976

Transport of L-cystine by cultivated skin fibroblasts of normal subjects and patients with cystinosis.

Uptake of L-cystine at the plasma membrane of fibroblasts derived from normal and cystinotic subjects was studied. L-Cystine accumulation after a 20-min period was increased in cystinotic fibroblasts incubated in 0.08 mM L-cystine. This effect appeared to be concentration-dependent since accumulation after 20 min at 0.004 mM concentration was decreased in cystinotic cells. Kinetic data suggested that at least two nondiffusional saturable processes with widely different substrate affinities mediate initial L-cystine uptake in skin fibroblasts. In addition, the transport process with high affinity for L-cystine may itself be a two-component system, as suggested by (1) additive inhibitory effect of other neutral amino acids, and (2) preincubation studies in which preincubation with cystathionine enhanced subsequent L-cystine uptake, whereas preincubation with other neutral amino acids depressed subsequent uptake. Affinity constants and maximal velocities of initial uptake did not appear to be altered in cells derived from patients with cystinosis. After 60-sec incubation with L-[35S] cystine, cystinotic cells retained more label as cystine than did normal cells at each concentration studied. These data indicate that initial L-cystine uptakein fibroblasts of patients with cystinosis proceeds at a normal rate by means of all transport systems currently shown to be present in normal cells.

Amino Acids↗

PubMed1977

The in vivo use of dithiothreitol in cystinosis.

Two male patients with late stage (uremic) infantile nephropathic cystinosis (INC) (Table 1) were treated by mouth with the reducing agent dithiothreitol (DTT), at doses not exceeding 25 mg-kg-1 body weight three times per day. Three sequential periods of observation were obtained in both patients: on thiol (8.5 months); off thiol (8-9 months); on thiol again (7 months or longer). Other than nausea and vomiting at the maximum dose range, no apparent toxicity was observed. One subject died in uremia in the 24th month of the study. The half-cystine concentration in peripheral blood leukocytes decreased during both treatment periods in each patient from initial pretreatment levels in excess of 8 nmol-mg-1 protein (normal less than 0.1 nmol-mg-1) to 10-20% of initial values (Table 2 and Fig. 1, A and B). Reduction in total number of blood leukocytes or in the neutrophil fraction, where cystine storage occurs selectively in cystinosis, did not occur (Table 3) as a possible explanation for these findings; nor did storage of samples, a possible artifact, influence the cystine content of cystinotic cells (Fig. 2). Multiple site rectal mucosa biopsy clearly revealed cystine storage but serial biopsies did not reflect a positive DTT response when compared with the leukocyte assay (Table 4). High intersample variation in cystine content, even between samples taken at one time, prevented measurement of a treatment response. DTT had no apparent detrimental effect on the concentration of representative proteins, including hemoglobin (Table 3), serum insulin, and serum immunoglobulin during the treatment trials. Renal function (glomerular and tubular) was severely depressed and did not improve during the period of observation in either patient (Table 2; Fig. 3, A and B). Postmortem tissues from one patient revealed 10-40-fold excess cystine accumulation in kidney cortex and liver (Table 5). However, these levels of accumulation are at the lower range of or even below published values for cystine in cystinotic kidney and liver. Whereas chemical methods are not reliable for detecting and measuring DTT in biologic fluids, preliminary evidence indicates that a silylated derivative of oxidized DTT can be detected in the urine of patients receiving DTT by mouth (Fig. 4). This finding suggests that the thiol is absorbed and excreted.

Autopsy↗

PubMed1988

A comparison of the effectiveness of cysteamine and phosphocysteamine in elevating plasma cysteamine concentration and decreasing leukocyte free cystine in nephropathic cystinosis.

Cysteamine (beta-mercaptoethylamine, MEA) is currently used to treat children with nephropathic cystinosis. In this study MEA was compared to phosphocysteamine (MEAP), a phosphorothioester that tastes and smells better than MEA, with respect to its ability to elevate plasma MEA and deplete leukocytes of cystine. Studies were performed in six children with nephropathic cystinosis ranging in age from 2 to 10 yr. After equimolar oral doses of either MEA or MEAP plasma cysteamine was determined at various times for 6 h. MEA was determined by sodium borohydride reduction followed by high-performance liquid chromatography separation and electrochemical detection. Leukocyte cystine was measured before and 1 and 6 h after drug administration. Peak plasma MEA was obtained 30 min to 1 h after a dose and was not significantly different when MEA (48.6 +/- 10.7, mean +/- SD) or MEAP (54.1 +/- 20.2) was given. Significant plasma MEA concentrations were seen as early as 15 min after an oral dose, indicating rapid absorption. Analysis of vomitus indicated that hydrolysis of the phosphate group of MEAP occurs in the stomach. The percent decrease in leukocyte cystine content obtained with MEA administration (61.9%) was not significantly different from the decrease observed when MEAP was administered (65.3%). MEA and MEAP appear to be equally effective in their cystine-depleting properties.

Administration, Oral↗

PubMed1991

Culture of renal tubular cells from the urine of patients with nephropathic cystinosis.

Nephropathic cystinosis represents a prototype for lysosomal storage diseases and is the most common cause of renal tubular Fanconi's syndrome. Mechanisms of the tubular transport defects in this disease have not been defined, however, in part because the cells readily cultured from affected patients, leukocytes and fibroblasts, do not express epithelial transport functions. Except for a single autopsy report, renal tubular cells from these patients have not been studied in vitro. In these studies, noninvasive harvesting and culture of renal tubular cells from the urine of patients with cystinosis is described. Cultures of renal tubular cells could be established from over 50% of the isolates which contained viable cells and which remained uncontaminated in vitro. Cells had an epithelial morphology in culture, and the majority of cultured cells expressed proximal tubular brush border marker enzyme. Cultured cells also expressed the storage defect in vitro, containing cystine levels up to 100 times those of normal cells. Cultured cells could be depleted of cystine by using the thiol cysteamine. This in vitro model system should be very useful for studying the mechanisms of renal tubular transport defects in this disease.

Cells, Cultured↗

PubMed1995

Metabolic studies of rat renal tubule cells loaded with cystine: the cystine dimethylester model of cystinosis.

The cause of Fanconi syndrome in cystinosis is enigmatic. It has previously been shown that renal tubules could be loaded with cystine by incubating them with cystine dimethylester (CDE), mimicking the biochemical hallmark of cystinosis. Such tubules have impaired transport, decreased whole-cell O2 consumption, and substrate utilization. In this study, the metabolic disturbances in cystine-loaded renal tubule cells were further characterized. Isolated rat renal tubules were loaded with cystine by incubating them with 2 mM CDE for 10 min. This had no significant effect on total ATPase, Na(+)-K(+)-ATPase, or the ouabain-insensitive ATPase activity of renal tissue homogenates from these cystine-loaded tubules. Intracellular K was significantly lower in the cystine-loaded tubules (37 +/- 2 versus 47 +/- 3 nEq/mg; P < 0.008). Intracellular ATP was reduced by 39% in the cystine-loaded tubules (23.7 +/- 2.4 versus 38.1 +/- 3.3 nmol/mg of protein; P < 0.0025). CDE (2 mM) reduced isolated mitochondrial O2 consumption with glutamate as the substrate by 66% (4.7 +/- 0.7 versus 13.9 +/- 0.8 nm/min per mg of protein, P < 0.001) but had no effect on mitochondrial O2 consumption with succinate as the substrate. It was speculated that the impaired transport from cystine loading with CDE is secondary to a decrease in energy generation.

Adenosine Triphosphate↗

PubMed1994

Cystinosis and gingival hyperplasia: demonstration of cystine crystals in gingival tissue and unusual aspects of management.

A patient with nephropathic cystinosis developed gingival hyperplasia secondary to cyclosporine-A therapy for his renal allograft. The typical crystals described on electron microscopic examination of other organs of patients with cystinosis were seen in the resected gingiva of this patient. These crystals have not been previously described in this location. Unusual aspects of the management of this patient are discussed.

Adult↗

PubMed1987

Nephropathic cystinosis: immunohistochemical and histopathologic studies of cornea, conjunctiva and iris.

Specimens of a cornea, conjunctiva and iris were removed at the time of penetrating keratoplasty in a case of nephropathic cystinosis. Immunohistochemical studies revealed the presence of class II antigens on the stromal keratocytes of the cornea and the vascular endothelial cells, pericytes and fibroblasts of the conjunctiva. In addition, there were thinning and focal breaks in Bowman's membrane. Both of these findings may have contributed to the severe photophobia and blepharospasm seen in patients with longstanding cystinosis.

Child↗

PubMed1987

Ocular changes in long-term evolution of infantile cystinosis.

Infantile cystinosis is an autosomal recessive lysosomal disorder of aminoacid metabolism leading to a storage of cystine crystals in the cells of many tissues, but mainly in the kidney and the eye. The ocular symptoms and long term evolution were studied in a series of 25 patients at the Enfants Malades Hospital. The follow-up over 26 years demonstrated that infantile cystinosis affected mainly corneal and retinal epithelium just as it affected the kidney epithelium. Corneal involvement was a constant finding after one year of age. It induced photophobia, which appeared between three and four years when a superficial punctate keratopathy appeared. A characteristic retinopathy was observed as early as three years of age. It was constantly present at seven years of age and caused loss of vision. When ERG results were compared to the most recent measurement of visual acuity, a correlation was observed between retinopathy and visual defect. For this reason, no corneal grafts were performed. The use of topic cysteamine appeared promising but no definitive conclusions could be made.

Adolescent↗

PubMed1975

Cystinosis of bone.

The authors describe a case of cystinosis of bone that presented initial difficulties in diagnosis. They discuss the clinical features and the radiographic appearances, which demonstrated numerous zones of osteoporosis with a markedly monomelic distribution in the left leg. The condition arose as a result of trauma. Numerous accumulations of intracellular cystine crystals were revealed by the ultramicroscopic study of bone fragments obtained by biopsy, and this led the authors to diagnose the case as cystine thesaurismosis of bone. The case is of interest not only because of its exceptional rarity (it is, perhaps, the first reported case of cystinosis localized exclusively in bone), but also because it was only possible to arrive at a diagnosis by means of ultramicroscopic investigation.

Adolescent↗

PubMed1992

[Infantile cystinosis. A new Tunisian case].

A case of cystinosis in a three and a half-year-old is reported. Suggestive manifestations included severe rickets, small stature, and complex renal tubule dysfunction meeting the criteria for secondary Fanconi syndrome. Diagnosis was established by the discovery of retinal lesions upon ophtalmologic evaluation and, above all, by the finding that intracellular leukocyte cystine levels were increased to 16 mumol of 1/2 cystine per gram protein. Cystinosis is severe because it inevitably leads to renal failure. Much hope is currently placed in the use of cysteamine to delay this and other complications. At present, early antenatal diagnosis during the first ten weeks of pregnancy is needed in high-risk families to allow elective termination of pregnancy within the legal time limit.

Child, Preschool↗

PubMed2006

[Cystinosis--an orphan disease. Pathogenesis and current treatment].

Cystinosis belongs to, so called, orphan diseases. It is an autosomal recessive lysosomal storage disease caused by defective transport of the amino acid cystine out of lysosomes. The stored cystine is poorly soluble and crystallizes within the lysosomes of many cell types, leading to widespread tissue and organ damage. Patients with the infantile nephropathic form of cystinosis (the most common and the most severe) develop symptoms early on in life and renal failure by late childhood. The current opinion about pathogenesis and treatment of the disease is described.

Adolescent↗

PubMedDate not supplied

Successful pregnancies in dialysis patients including those suffering from cystinosis and familial Mediterranean fever.

For women on maintenance dialysis, pregnancy is still uncommon. The outcome of such pregnancies has improved in recent case series. Here, we report in detail the treatment of five successful pregnancies in dialysis patients from our centre. The present case series also includes the first successful pregnancy of a dialysis patient with underlying familial Mediterranean fever, and of a dialysis patient with cystinosis. We treated all patients with an intensified hemodiafiltration protocol, increased erythropoietin dosages, a generous application of water-soluble vitamins and trace elements in addition to a multidisciplinary clinical management approach with a very low threshold for hospital admission. Specifically, we report treatment of arterial hypertension with respect to changes in dry weight and pharmacological therapy. Mean gestational age at delivery was 32.8+/-3.3 weeks and mean birth weight was 1,765+/-554 g. All mothers and newborns were discharged healthy and in good condition. These modified management guidelines have led to a favourable outcome in all our patients including two patients with familial Mediterranean fever and with cystinosis, and may help to guide therapy in other pregnant dialysis patients.

Adult↗

PubMed1976

[Cystinosis (author's transl)].

Cystinosis (syn. crystine storage disease) is inherited as an autosomal recessive trait. The severety of clinical symptoms may vary considerably. The most severe form of nephropathic cystinosis causes death of the affected patients at the age of 2 to 4 years (subacute course) or before puberty (primary chronical course). Three autopsy cases are demonstrated. Each of these children died from complications of chronic renal failure, caused by kidney contraction as a sequela of chronic interstitial nephritis. Cristalline cystine deposits were found in the renal interstium as well as in the RES cells of spleen and liver. Because of water solubility of L-cystine aqueous fixation and staining solutions must be avoided. Diagnostic doubly refractive brick- or needle-shaped cystine cristals can be demonstrated in frozen sections or tissue smears from spleen, liver, lymphnode and bone marrow.

Child↗

PubMedDate not supplied

Cystinosis with crystal-induced synovitis and arthropathy.

A clinically and experimentally verified intermediary form of cystinosis is described. A 30-year old patient has been examined initially for eye complications confined to the frontal segment of the eye on the cornea and conjunctiva. The joint disease received no attention despite the fact that the motor apparatus of the patient was involved from her childhood. As regards the arthrology, the disease can be classed among crystal-induced synovitis and arthropathy. The lesion of the tubular apparatus of the kidney, which cannot transform vitamin D into its active form, represents an important factor in the genesis of osteoporosis. A description of the intermediary from of cystinosis with eye, kidney and joint symptoms was not found in the literature.

Adult↗