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PubMed1981

Association of certain human leukocyte antigens with nephropathic cystinosis in the absence of linkage between these loci.

The HLA phenotypes of 41 patients (22 males and 19 females) with classical nephropathic cystinosis were analyzed and compared with those reported from a control group of 1,465 Americans of Caucasian origin. There was a significantly increased association of cystinosis with HLA B7, and a reduced association with A9. The calculated A3B7 and A1B7 haplotypes were also significantly increased in cystinosis. Lod score analysis of five families indicated that linkage between the gene(s) for cystinosis and the HLA loci is unlikely. While associations of other genetic diseases with specific HLA types should be sought, such relationships, as documented here, do not imply true genetic linkage.

Cystinosis↗
PubMed1994

Hepatic fibrosis associated with hereditary cystinosis: a novel form of noncirrhotic portal hypertension.

Hepatomegaly is a common feature of hereditary nephropathic cystinosis but is rarely associated with symptoms of liver disease. Aside from cystine crystal deposit within Kupffer cells, the cause of liver enlargement is unknown. We report the case of a patient with nephropathic cystinosis who died at the age of 24 yr after multiple renal transplants. In addition to classical systemic signs of advanced cystinosis, the patient had evidence of portal hypertension. At autopsy, the liver was enlarged for body size (1520 g) and very firm. Massive crystal accumulation within Kuppfer cells was accompanied by intense sinusoidal deposition of collagen types I, III, and IV, with associated hepatocyte atrophy. There was no inflammation or regenerative nodules. Numerous enlarged and fat-laden Ito cells were present in association with the collagen. This case illustrates a novel form of noncirrhotic portal hypertension associated with cystinosis. Analysis of future cases may serve to highlight the role of Kupffer and Ito cells in the pathogenesis of hepatic fibrosis.

Adult↗
PubMedDate not supplied

A patient with cystinosis presenting transient features of Bartter syndrome.

A 16-month-old boy was admitted to the clinic because of vomiting and growth failure. His weight and height measurements were under the fifth percentile. He had fair hair and skin, enlarged wrists and rachitic rosaries. The presence of metabolic alkalosis, hypokalemia, hypochloremia, and high renin and aldosterone levels were suggestive of Bartter syndrome. However, in view of the growth failure, fair hair and skin, proteinuria, polyuria and active rickets, cystinosis was considered. Bone marrow smear examination was normal, despite the existence of suspicious crystals in the cornea. Cystine crystals were seen in the conjunctiva biopsy and increased leukocyte cystine level was measured; therefore, definitive cystinosis diagnosis was made. Renal Fanconi syndrome with metabolic acidosis is prominent in cystinosis; however, in rare instances, if sodium-dependent trans-tubular transport defect is present, patients could have Bartter syndrome findings such as hypochloremic metabolic alkalosis. Our case is a good example demonstrating that metabolic alkalosis should not exclude cystinosis and the other signs and symptoms of the patient should be thoroughly evaluated.

Bartter Syndrome↗
PubMed2001

Long-term treatment with growth hormone in short children with nephropathic cystinosis.

OBJECTIVE: The objective was to assess the efficacy and safety of growth hormone (GH) treatment in severely growth retarded children with nephropathic cystinosis during conservative treatment and during renal replacement therapy. STUDY DESIGN: The design was an open-labeled prospective trial with a run-in period of 1 year. RESULTS: A total of 74 children with cystinosis (age 3.0 to 18 years) were treated with GH over a mean period of 3.1 years (range 1 to 10 years); 52 patients were receiving conservative treatment (mean age 7.1 years), 7 were receiving dialysis (12.5 years), and 15 had received a renal transplant (14.8 years). The mean standardized height (SD score) was -4.0 in the conservative treatment group, -4.4 in the dialysis group, and -4.9 in the renal transplant group. During the first treatment year, height velocity doubled in the conservative treatment group, increased by 80% in the dialysis group, and increased by 45% in renal transplant group. Within 3 years the height SD score increased by +1.6 (P <.001) in prepubertal patients receiving conservative treatment, and percentile parallel growth was maintained thereafter. These effects of GH were less expressed in peripubertal patients receiving renal replacement therapy. No major side effects were observed. CONCLUSION: Long-term GH treatment is safe and effective in young children with nephropathic cystinosis. GH treatment should be started early in the course of the disease if adequate nutrition and cysteamine treatment do not prevent growth retardation.

Adolescent↗
PubMed2000

Ultrasound biomicroscopy of the eye in cystinosis.

OBJECTIVE: To describe the ocular ultrasound biomicroscopy (UBM) findings in patients with cystinosis. METHODS: Six patients with infantile nephropathic cystinosis, aged 16 to 25 years, and 6 controls (matched for age and spherical refractive error) were examined clinically and with UBM. Scleral reflectivity, corneal and iris thickness, central anterior chamber depth, angle width, trabecular meshwork to ciliary process distance, and ciliary sulcus width were measured. RESULTS: No patient had glaucoma or posterior synechiae, but all had crystals in the trabecular meshwork apparent with gonioscopy. Using UBM, the cornea and iris appeared similar in both groups, but the scleral reflectivity was increased in patients (P =.003). The angle was narrower in patients (mean +/- SD, 20 degrees +/- 7 degrees ) than controls (31 degrees +/- 5 degrees, P<. 001). The anterior chamber was shallower in patients (2556 +/- 197 microm) than controls (2968 +/- 284 microm, P<.001). The ciliary sulcus was closed or narrow in all patients (83 +/- 112 microm) compared with controls (339 +/- 135 microm, P<.001), with a reduction in the trabecular meshwork to ciliary process distance. CONCLUSIONS: This report of ocular UBM findings in cystinosis demonstrated narrowing of the angle and a ciliary body configuration similar to that reported for plateau iris syndrome. Gonioscopy demonstrated crystals in the trabecular meshwork. These findings may explain the predisposition of these patients to glaucoma.

Adolescent↗
PubMed1987

Pancreatic endocrine insufficiency in posttransplant cystinosis.

Nephropathic cystinosis causes renal death by approximately age 10 years. With increased life span due to kidney transplantation, ten to 25 years of cystine accumulation has resulted in pancreatic complications in individuals with cystinosis. We noted severe hyperglycemia in five posttransplant patients, three of whom remained insulin-dependent diabetics several years after transplant. The clinical findings were not consistent with steroid-dependent or insulin-resistant diabetes. Pancreatic cystine deposition was detected histologically and biochemically on post-mortem examination of two other patients. We conclude that hyperglycemia may be anticipated in the immediate posttransplant period in cystinotic patients and that some patients will require insulin therapy years later. The use of cystine-depleting agents should be considered in posttransplant cystinosis as an attempt to prevent potential damage to the pancreas and other organs from cystine deposition.

Adolescent↗
PubMed1994

Distal vacuolar myopathy in nephropathic cystinosis.

Nephropathic cystinosis is a lysosomal storage disorder leading to renal failure by age 10 years. Prolonged patient survival following renal transplantation has allowed the development of previously unknown long-term complications. Muscle involvement has been reported in a single posttransplant cystinosis patient, but the range of clinical, electrophysiologic, and histologic features has not been fully described. Thirteen of 54 post-renal-transplant patients that we examined developed weakness and wasting in the small hand muscles, with or without facial weakness and dysphagia. Tendon reflexes were preserved and sensory examinations were normal. Electrophysiologic studies in 11 affected patients showed normal nerve conduction velocities and preserved sensory action potentials. The voluntary motor units in the affected distal muscles had reduced amplitude and brief duration, confirmed with quantitative electromyography in 4 patients. Biopsy of the severely affected abductor digiti minimi or extensor carpi radialis brevis muscles in 2 patients revealed marked fiber size variability, prominent acid phosphatase-positive vacuoles, and absence of fiber type grouping or inflammatory cells. Crystals of cystine were detected in perimysial cells but not within the muscle cell vacuoles. The muscle cystine content of clinically affected muscles was markedly elevated. We conclude that a distal vacuolar myopathy is a common late complication of untreated nephropathic cystinosis. Although the cause is unclear, the general lysosomal defect in this disease may also affect the lysosomes within muscle fibers.

Adolescent↗
PubMed2005

Prenatal diagnosis of cystinosis by quantitative measurement of cystine in chorionic villi and cultured cells.

OBJECTIVE: Prenatal diagnosis of cystinosis has been available for over 30 years by the incubation of cultured amniotic cells, intact chorionic villi and cultured chorionic cells with [35S]-cystine followed by thin layer chromatography and visual inspection of autoradiographs of the chromatograms for cystine. This method has proved highly reliable but because of the short half-life of [35S]-cystine, its cost and the length of the assay procedure, an alternative method of diagnosis was investigated. METHOD: Cystine was quantitatively measured in chorionic villi directly, in cultured chorionic villi and cultured amniotic cells using a cystine-binding protein from Escherichia coli. RESULTS: Twelve pregnancies at risk for cystinosis were monitored by both the [35S]-cystine uptake method and the new quantitative method in uncultured chorionic villi. There was no discrepancy between the results obtained with the two methods and subsequently 15 pregnancies have been monitored by the quantitative assay only--13 in chorionic villi directly, 1 in cultured chorionic villi cells and 1 in cultured amniotic cells. Grossly elevated levels of cystine were found in seven pregnancies. CONCLUSION: An unequivocal diagnosis of cystinosis can be made within 24 h of sampling by the quantitative measurement of cystine in uncultured chorionic villi.

Abortion, Eugenic↗
PubMed1999

Identification and detection of the common 65-kb deletion breakpoint in the nephropathic cystinosis gene (CTNS).

The most common mutation in the cystinosis gene, CTNS, is a 65-kb deletion thought to have originated in Germany. Although homozygotes for this deletion are detectable by the absence of the D17S829 polymorphic marker, no method exists to identify heterozygotes. We identified the 65-kb deletion breakpoints and used flanking PCR primers to amplify a 423-bp fragment present only in the deletion alleles. Using this method, we determined that 121 of 216 (56%) cystinosis alleles examined bore the 65-kb deletion. We found no non-Europeans with the deletion, and the deletion size and breakpoints appeared identical in all patients studied, supporting the concept of a founder effect. The addition of D17S829 primers (266 bp apart) to the PCR created a multiplex PCR system useful for diagnosing cystinosis patients homozygous and heterozygous for the 65-kb deletion.

Alleles↗
PubMed1999

Mutations of CTNS causing intermediate cystinosis.

Six patients with the intermediate form of cystinosis are described. Two have new mutations not previously described. The disease occurs due either to the combination of one mild mutation and one which is known to cause nephropathic cystinosis or to homozygosity for a predicted mild mutation. Partial phenotypic correction of cystinotic fibroblasts by transfection with normal cDNA or a cDNA derived from a mutation causing intermediate cystinosis is demonstrated.

Adolescent↗
PubMed1982

Brain lesions in a case of cystinosis.

Cystinosis usually spares the brain or causes only deposition of cystine crystals without destructive lesions in choroid plexus or, rarely, in brain parenchyma. A case of cystinosis is presented with unusually long survival and with bilateral necrosis, numerous concretions, and extensive demyelination of internal capsule and brachium pontis. No cystine crystals could be demonstrated in these lesions although they were present in the choroid plexus. The symmetry and unique distribution of the lesions as well as their histopathology suggested a progressive process caused by the metabolic dysfunction of cystinosis. The validity of this hypothesis will be determined by future experience as renal transplants enable more patients to survive into adult life.

Adult↗
PubMed1995

Medullary nephrocalcinosis in nephropathic cystinosis.

Children with nephropathic cystinosis excrete large amounts of calcium and phosphate due to renal tubular Fanconi syndrome, and also receive substantial supplements of phosphate and alkalinizing agents. Since these constitute risk factors for nephrocalcinosis, we evaluated 41 children age 2 months to 15 years with nephropathic cystinosis and good renal function by performing retroperitoneal ultrasound examinations in a blinded fashion. We also retrospectively analyzed parameters of calcium and phosphate metabolism representing 216 person-years of data on these children. Fifteen children had no evidence of medullary nephrocalcinosis, while 18 had mild nephrocalcinosis, and 8 severe nephrocalcinosis; 5 had renal stones. Mean urine calcium and phosphate concentrations increased from 1.47 mM and 5.30 mM, respectively, in children without nephrocalcinosis to 1.60 mM and 5.69 mM in children with mild nephrocalcinosis to 1.66 mM and 6.19 mM in children with severe nephrocalcinosis. Mean urine pH ranged from 7.5 to 8.1. The mean (+/- SD) age of the 26 patients with nephrocalcinosis was 9.4 +/- 3.8 years compared with 5.1 +/- 3.8 years for those without nephrocalcinosis (P < 0.005). Serum calcium, phosphate, vitamin D, and parathyroid hormone did not correlate with frequency or degree of nephrocalcinosis. We conclude that nephrocalcinosis frequently accompanies nephropathic cystinosis, can be detected by ultrasound examination, and might be managed by reducing oral replacement of phosphate, calcium, vitamin D, and citrate. Consideration should be given to truncating phosphate replacement once bone growth ceases.

Adolescent↗
PubMed1996

Clinical polymorphism of cystinosis encephalopathy. Results of treatment with cysteamine.

Of the 26 cystinotic patients over 19 years of age followed in our institution, 7 developed CNS complications at a mean age of 23 years. Two forms were observed. The first, associating cerebellar and pyramidal signs, mental deterioration and finally pseudo-bulbar palsy, may be called cystinosis encephalopathy. The other form resembled a stroke-like episode with coma and hemiplegia or milder symptoms. Hydrocephalus was rare and not associated with clinical symptoms in this series. Cysteamine was administered for longer than 6 months to 4 of the patients with encephalopathy. Two had an almost complete disappearance of their symptoms including the gross abnormalities of MR imaging in one; one improved partially and remained stable, and one continued to deteriorate but was suspected of non-compliance. These results suggest that cysteamine may be an effective treatment of cystinosis encephalopathy and encourage prescription of this drug in cystinosis in order to prevent this complication.

Adolescent↗
PubMed2003

New aspects of the pathogenesis of cystinosis.

Cystinosis is a lysosomal transport disorder characterized by an intra-lysosomal accumulation of cystine, the disulfide of the amino acid cysteine. It is the most common inherited cause of the renal Fanconi syndrome. There are various clinical forms, infantile, juvenile, and ocular, based on age of onset and severity of symptoms. The first clinical description appeared in the early 1900s, but it was not until 1998 that the causative gene, CTNS, was identified. CTNS encodes cystinosin, a novel seven transmembrane domain (TM) protein. Cystinosin is a lysosomal membrane protein that requires two lysosomal targeting signals: a classic GYDQL motif in its C-terminal tail and a novel conformational motif, the core of which is YFPQA, situated in the fifth inter-TM loop. Cystinosin is the lysosomal cystine transporter and its activity is H(+)-driven. A mouse model of cystinosis was recently generated and Ctns(-/-) mice accumulate cystine in all tissues. A high level of cystine accumulates in the kidney, but these mice do not present with proximal tubulopathy or renal dysfunction. The Ctns(-/-) mouse model may provide clues to the cause of the Fanconi syndrome associated with cystinosis, the origin of which remains poorly understood.

Amino Acid Transport Systems, Neutral↗
PubMed1997

The effects of cysteamine on the upper gastrointestinal tract of children with cystinosis.

The purpose of this study was to evaluate the effects of cysteamine on gastric acid output and serum gastrin levels in children with nephropathic cystinosis. We studied four children with nephropathic cystinosis receiving a dose of free base cysteamine of 14.35 mg/kg four times a day (range 12.30-18.80 mg/kg). Gastric acid was measured for the hour before and after administration of the medication. Serum gastrin levels were obtained at 0, 30, 60, and 90 min following the medication. Gastrointestinal anatomy was evaluated by endoscopy and biopsy. Following administration of the medication, all subjects showed an increase in gastric acid output. Mean acid output increased from 0.79 to 2.22 mEq/h. Mean gastric acid output adjusted for body weight increased from 0.03 to 0.09 mEq/kg per hour. Following administration of the medication, all subjects showed an increase in serum gastrin. The mean increase above the base value was 38.3 pg/dl. Two of the four subjects demonstrated visual and histological evidence of inflammation. Cysteamine has a marked effect on gastric acid production and serum gastrin, even at the dose used in children with nephropathic cystinosis. The clinical effect of this acid production is unknown but may be significant.

Adolescent↗
PubMed1998

Feeding problems in cystinosis.

Nephropathic cystinosis, a rare autosomal recessive storage disease characterized by intracellular storage of free cystine due to a defect in lysosomal cystine transport, is the most common cause of Fanconi syndrome in childhood. Although manifestations of extrarenal organ involvement during the course of the disease are diverse, the spectrum of gastrointestinal (GI) problems has not yet been examined. In responses to a questionnaire from 70 (35%) of the 200 registered members of the Cystinosis Foundation, we found that GI symptoms are more common, more diverse, and occur at a younger age in patients with cystinosis than previously recognized. Ninety-three percent of interviewed subjects had GI symptoms at initial presentation, and the overall lifetime prevalence of GI problems in this group was 100%. Thirty percent have received gastric/jejunal tube feedings, and 7% required continuous or intermittent total parenteral nutrition. Fifty percent have been formally tested for GI abnormalities, and among these 77% have documented functional abnormalities (reflux/dysmotility, pseudo-obstruction, swallowing dysfunction). Early recognition and aggressive therapy of GI problems in cystinotic patients may ameliorate or prevent the development of disabling symptoms.

Adolescent↗
PubMed1977

Cadaver renal transplantation in children with cystinosis.

Five children with end-stage renal disease resulting from cystinosis received seven cadaver renal allografts. Four recipients have functioning grafts eight to 55 months after receiving the transplant and one recipient lost two grafts at 17 and 26 months after the transplant. There was no florid recurrence of the Fanconi syndrome although proximal renal tubular dysfunction developed in two patients, in one in association with chronic rejection and in one without apparent etiology. Free cystine content of white blood cells, cultured skin fibroblasts and allograft tissue was significantly increased. Cystine crystals were observed in the mesangium of two grafts and in the interstitial tissue of all grafts; however, no cystine crystals were found in the tubules. The location of the cystine crystals, as well as the fact that the highest free level of cystine of allograft tissue was observed in the graft undergoing chronic rejection. led to the hypothesis that recipient cells infiltrating the graft were the source of cystine deposition. The data indicate that successful cadaveric transplantation does not correct the primary metabolic defect in cystinosis, thereby explaining the persistence of the extrarenal clinical manifestations, such as photophobia and hypothyroidism, after renal transplantation in cystinosis.

Bone Diseases↗
PubMed1987

Nephropathic cystinosis with central nervous system involvement.

Nephropathic cystinosis is associated with end-stage renal failure, retinal damage, and hypothyroidism. Patients may now survive past the first decade of life with the use of dialysis and renal transplantation. Examination of a 24-year-old woman with this disorder revealed ovarian failure, mildly abnormal results on a glucose tolerance test, intermittent confusion, short-term memory loss, and cerebral atrophy on computerized axial tomography. Autopsy examination at age 25 years revealed cystine storage in multiple tissues including the atrophic ovaries, pancreatic islet cells, the aorta, and the brain. Dysfunction of multiple organ systems may develop in patients with cystinosis who survive into adulthood. This emphasizes the need for a systemic therapy for cystinosis.

Adult↗