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PubMed1987

Corneal sensitivity in nephropathic cystinosis.

We measured corneal sensitivity in 14 patients with infantile nephropathic cystinosis and in 13 age-matched controls. All patients with cystinosis had the pathognomonic anterior segment findings of crystal deposition within conjunctiva and cornea. Transcutaneous stimulation of the supraorbital nerve and surface electromyographic recording of the orbicularis oculi muscle performed on four patients showed a normal afferent limb to the blink reflex. The corneal sensitivity in patients with cystinosis was 3.18 g/mm2; in the control subjects it was 0.43 g/mm2. This difference was statistically significant (P less than .001).

Adolescent↗
PubMed1993

Renal transplantation for infantile cystinosis: long-term follow-up.

Renal transplantation for infantile cystinosis corrects renal failure and prolongs survival. However, after transplantation, the disease may develop in the allograft and continue to progress in nonrenal organs. We studied seven children (6 boys, 1 girl) with infantile cystinosis who received 11 renal transplants (3 cadaver, 8 living-related) between May 1969 and December 1986. The age at transplant ranged from 6 to 12 years (mean, 9.1 years). Four children received second renal transplants at a mean age of 17 years (range, 16 to 22 years). The mean period of follow-up was 138 +/- 47 months. Three children received cysteamine therapy prior to transplantation. Nonrenal complications of infantile cystinosis present before transplantation were photophobia (n = 3), corneal crystals (n = 5), hypothyroidism (n = 1), rickets (n = 6), and short stature (n = 7). Graft and patient survival did not differ from controls matched for the time of transplantation. Two patients died (1 pneumococcal sepsis, 1 respiratory failure due to pulmonary fibrosis) with functioning grafts 5 and 14 years posttransplant. Complications that developed posttransplant included photophobia (n = 1), corneal crystals (n = 2), hypothyroidism (n = 4), polyneuropathy (n = 1), pulmonary fibrosis (n = 1), abnormal electroencephalogram without clinical seizures (n = 1), bladder stones (n = 1), and diabetes mellitus (n = 2). One patient received a corneal transplant. All seven children failed to show improvement in growth following transplantation. Cystine crystals are present in graft-infiltrating cells, but do not seem to affect kidney allograft function.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗
PubMed1977

Endocrine studies in cystinosis: compensated primary hypothyroidism.

Children with nephropathic cystinosis exhibit marked growth retardation. Improved medical management and renal transplantation have increased their life expectancy beyond the second decade. We have studied endocrine function in seven patients with cystinosis and reviewed autopsy findings of four patients and medical records of 24 others. One 10-year-old boy was overtly hypothyroid. The six other patients had normal studies of peripheral thyroid function but two had borderline and two had frankly elevated serum TSH levels. Stimulation tests of cortisol and growth hormone secretion and basal levels of serum NSILA-s were normal. Postmortem histology of the thyroid glands revealed extensive destruction and infiltration of the epithelium with cystine crystals. Despite the presence of cystine crystals in other endocrine tissues, there was no destruction of epithelium in glands other than in the thyroid. We conclude that in nephropathic cystinosis "compensated" primary hypothyroidism occurs frequently and early and may be diagnosed by measurement of serum TSH concentrations.

Child↗
PubMed2003

Steady-state pharmacokinetics and pharmacodynamics of cysteamine bitartrate in paediatric nephropathic cystinosis patients.

AIMS: Cysteamine is used to reduce tissue cystine content in patients suffering from nephropathic cystinosis. The objectives of the current study were to investigate pharmacokinetics and pharmacodynamics of cysteamine bitartrate in children and young adults with nephropathic cystinosis. METHODS: Cysteamine bitartrate was administered to 11 cystinosis patients at their regular dose level in a single-dose, open-label, steady-state study. Blood samples were collected and analysed for plasma cysteamine and white blood cell cystine content and pharmacokinetic and pharmacodynamic parameters estimated by NONMEM analysis using a linked pharmacokinetic-pharmacodynamic model. RESULTS: Cysteamine was rapidly cleared from the plasma (mean CL/F = 32.3 ml min(-1) kg(-1), range = 17.3-52.2), appeared to be extensively distributed (mean Vss/F = 15.1 l, range 2.7-32.3) and exhibited a mean Tmax of 1.4 h. White blood cell cystine content post-dosing was significantly decreased compared with pre- and post-dose values (average decrement approximately 47%). A counter-clockwise hysteresis was noted in all patients, suggestive of a lag time (mean Tlag = 0.44 h, range 0.22-0.92) between drug concentration and effect. CONCLUSIONS: The results of this study establish that cysteamine is rapidly cleared from the plasma but that an every 6 h dosing interval adequately maintains white blood cell cystine content below the target of 1 nmol cystine per mg protein.

Adolescent↗
PubMed1987

Removal of corneal crystals by topical cysteamine in nephropathic cystinosis.

In patients with nephropathic cystinosis, corneal crystals develop by one year of age; they progressively accumulate and eventually cause recurrent corneal erosions and photophobia. After an in vitro study of cystinotic corneal stromal cells showed cystine depletion by cysteamine and after topical cysteamine was determined to be nontoxic in rabbits, we performed a controlled double-blind clinical trial of 10 mM cysteamine eyedrops in young patients with cystinosis, using one eye for treatment and the other as the control. Two children begun on the protocol before two years of age had a striking decrease in the number of corneal crystals in the cysteamine-treated eye within four to five months of entering the study. Cysteamine eyedrops appear to be safe and efficacious in the short-term treatment of patients with cystinosis who are under two years of age. The long-term value of such treatment and its effectiveness in older patients remain to be determined.

Administration, Topical↗
PubMed1993

Improved renal function in children with cystinosis treated with cysteamine.

BACKGROUND: The lysosomal storage disease cystinosis results in renal failure at approximately 10 years of age. Although oral cysteamine therapy is recognized to preserve kidney function, the extent of renal benefit has not been determined. METHODS: Between 1960 and 1992, we determined 24-hour creatinine clearances in 76 children with cystinosis during 1081 admissions to the National Institutes of Health. Seventeen children were considered to have received adequate treatment with cysteamine, since they had depletion of cystine from leukocytes and began therapy before the age of 2 years; treatment lasted a mean of 7.1 years. Thirty-two children were considered to have received partial treatment, since they had poor compliance with therapy or began treatment after the age of 2; treatment lasted a mean of 4.5 years. Twenty-seven children were followed in the era before cysteamine therapy and thus never received cysteamine. RESULTS: Of the 27 children who never received cysteamine, 16 were followed at the National Institutes of Health until renal failure occurred; their mean (+/- SD) creatinine clearance was 8.0 +/- 4.8 ml per minute per 1.73 m2 of body-surface area at a mean age of 8.3 +/- 1.9 years. Of the 17 children who received adequate treatment, none had renal failure; their mean creatinine clearance was 57 +/- 20 ml per minute per 1.73 m2 at 8.3 +/- 3.8 years of age. The mean creatinine clearance of the children who received partial or adequate treatment with cysteamine increased with age up to the age of five years and then declined linearly with age at a normal rate. For the children who received adequate treatment, the mean creatinine clearance was predicted to reach 0 ml per minute per 1.73 m2 at the age of 74 years, as compared with 20 years of age for the children who received partial treatment. With no therapy, the mean creatinine clearance reaches 0 ml per minute per 1.73 m2 at 10 years of age. CONCLUSIONS: Children with cystinosis who are treated early and adequately with cysteamine have renal function that increases during the first five years of life and then declines at a normal rate. Patients with poorer compliance and those who are treated at an older age do less well.

Child↗
PubMed2002

Age-related prevalence of anterior segment complications in patients with infantile nephropathic cystinosis.

PURPOSE: As a result of successful renal transplantation, patients with nephropathic cystinosis are now living into adulthood. As these patients age, anterior segment ocular complications, other than deposition of corneal crystals, become more evident. With our experience with 172 patients followed up at the National Institutes of Health between 1976 and 2000, the prevalence of anterior segment complications in nephropathic cystinosis was determined. METHODS: A cross-sectional examination of age-specific prevalence was performed with logistic regression analysis of prevalence change with age. RESULTS: Besides the corneal crystals apparent in all age groups, superficial punctate keratopathy, filamentary keratopathy, severe peripheral corneal neovascularization, band keratopathy, and posterior synechiae with iris thickening and transillumination were noted in the older age groups. The prevalence increased with age for each complication. CONCLUSIONS: As patients with cystinosis grow older, more severe ophthalmic manifestations become evident. It remains to be seen how the prevalence of these complications will be altered by early initiation of oral and topical cysteamine therapy.

Adolescent↗
PubMed1995

Intraoperative hyperthermia in a paediatric patient with cystinosis.

Cystinosis is a rare autosomal recessive inherited disorder of amino acid metabolism. Little is known of the affects of general anaesthesia on the disease (Tobias 1993) and complications relating to anaesthesia have not been previously reported. Infantile cystinosis presents as progressive renal failure and the Fanconi syndrome and metabolic bone disease often develop. We describe the case of a child who presented with signs of apparent malignant hyperthermia (MH) under general anaesthesia and was treated with dantrolene. During a repeat 'trigger-free' general anaesthetic he developed a fever which responded to paracetamol. The metabolic effects of cystinosis and its similarity to MH will be discussed.

Anesthesia, General↗
PubMed2004

[Cystinosis: diagnosis through the measurement of the leukocyte cystine content by HPLC].

BACKGROUND AND OBJECTIVE: Cystinosis is an autosomal recessive disorder characterized by an accumulation of intralysosomal cystine. Three disease forms exist, infantile, juvenile or late-onset, and ocular nonnephropathic cystinosis, delineated on the basis of severity of symptoms and age of onset. The knowledge of early clinic manifestations and the onset of the appropriate therapy delay the evolution of the disease and improve the general conditions. Therefore, it is necessary to develop a sensible diagnostic method for early detection and treatment of the disease. CLINICAL CASE AND METHODS: The leukocyte cystine content was determined by HPLC in a 42 years old female patient after renal transplantation, and with the clinical characteristic complications of the intermediate cystinosis. Equally, the molecular characterization of the structural defects of the cystinosin (CTNS) gene was made in the patient and in all family members. RESULTS: By measuring of the leukocyte cystine content in the patient and family members, we have determined 5 family members as heterozygous. This result was confirmed by molecular analysis that showed the approximately 65 kb deletion in the 5 family members. The patient was heterozygous for the approximately 65 kb deletion, and the second alteration was not determined. CONCLUSIONS: We presented a useful diagnostic method, based in the determination of cystine content of polymorphonuclear leukocytes, which permits to detect the heterozygous individuals.

Adult↗
PubMed1981

Kidney transplantation in uremic children with cystinosis.

10 children underwent cadaveric renal transplantation between the ages of 8.0 and 12.5 years for uremia secondary to infantile cystinosis. 6 children are doing well 6-62 months after-transplantation. 3 of the 4 other recipients required a second graft and eventually died of uremia or fulminant viral encephalitis, the other lost her first graft due to accelerated acute rejection and is now on maintenance hemodialysis. No further systemic complications of cystinosis have been observed in the patients with functioning grafts. Our experience confirms that kidney transplantation is the treatment of choice for uremic children with infantile cystinosis.

Cadaver↗
PubMed1988

Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome.

11 children with either cystinosis or Lowe's syndrome had a reduced content of plasma and muscle carnitine due to renal Fanconi syndrome. After treatment with oral L-carnitine, 100 mg/kg per d divided every 6 h, plasma carnitine concentrations became normal in all subjects within 2 d. Initial plasma free fatty acid concentrations, inversely related to free carnitine concentrations, were reduced after 7-20 mo of carnitine therapy. Muscle lipid accumulation, which varied directly with duration of carnitine deficiency (r = 0.73), improved significantly in three of seven rebiopsied patients after carnitine therapy. One Lowe's syndrome patient achieved a normal muscle carnitine level after therapy. Muscle carnitine levels remained low in all cystinosis patients, even though cystinotic muscle cells in culture took up L-[3H]carnitine normally. The half-life of plasma carnitine for cystinotic children given a single oral dose approximated 6.3 h; 14% of ingested L-carnitine was excreted within 24 h. Studies in a uremic patient with cystinosis showed that her plasma carnitine was in equilibrium with some larger compartment and may have been maintained by release of carnitine from the muscle during dialysis. Because oral L-carnitine corrects plasma carnitine deficiency, lowers plasma free fatty acid concentrations, and reverses muscle lipid accumulation in some patients, its use as therapy in renal Fanconi syndrome should be considered. However, its efficacy in restoring muscle carnitine to normal, and the optimal dosage regimen, have yet to be determined.

Administration, Oral↗
PubMed1985

Cystinosis presenting with features suggesting Bartter syndrome. Case report and literature review.

Features suggestive of Bartter syndrome (hypokalemia, hypochloremic metabolic alkalosis, and normal blood pressure despite hyperreninemia and hyperaldosteronism) were found in a 5-year-old black child with cystinosis and Fanconi syndrome. Review of his medical records revealed that these abnormalities had probably been present when he first became clinically ill at 2 years of age. Sodium and potassium chloride supplementation lead to improved growth and strength, partial correction of his electrolyte abnormalities, and a decrease in markedly elevated plasma renin activity. Literature review disclosed a similar presentation in four Caucasian children with cystinosis. Biochemical findings compatible with Bartter syndrome can occur together with evidence of generalized proximal renal tubular dysfunction (Fanconi syndrome) in nephropathic cystinosis.

Anemia, Aplastic↗
PubMedDate not supplied

A cost-effectiveness analysis of the orphan drug cysteamine in the treatment of infantile cystinosis.

OBJECTIVE: Cysteamine is a recently licensed orphan drug used to treat the inherited metabolic disease cystinosis. The drug delays the onset of renal failure in cystinotic patients and may provide many other significant health benefits. This study examined the cost-effectiveness of the administration of cysteamine to cystinotic patients prior to end-stage renal disease (ESRD). METHOD: Decision-tree analysis and cost-effectiveness analysis. Cost data were estimated from current clinical charges and Medicare public-access reports. Life expectancy outcomes were derived from both published and unpublished clinical studies and from the U.S. Renal Data System. RESULTS: Cysteamine therapy can extend the life of kidneys and delay renal transplantation, thereby increasing life expectancy for patients with cystinosis. Patients receiving cysteamine therapy prior to renal failure have lifetime-treatment drug costs of $234,000, in comparison with $238,000 for those who are not medicated. Costs of cysteamine therapy are offset by savings associated with delaying transplantation and costs of dialysis. CONCLUSIONS: Use of the orphan drug cysteamine both improves health outcomes and reduces health care costs for patients with cystinosis.

Child↗
PubMed1980

Pituitary resistance to thyroid hormone in cystinosis.

Eleven children with nephropathic cystinosis without clinical features of hyperthyroidism or hypothyroidism had elevated serum levels of immunoreactive TSH. The mean TSH level (+/- SE) was 37.4 +/- 12.3 microM/ml. Serial determinations of thyroid function during 1 yr were: mean (+/- SE) serum T4, 10.8 +/- 0.7 microgram/dl; free T4, 2.1 +/- 0.2 ng/dl; and T3, 239 +/- 6 ng/dl. After 500 microgram TRH iv, the peak TSH level exceeded 100 microU/ml in 6 of 10 patients, whereas T3 responses were variable. Studies of parameters influenced by thyroid hormone, including red cell sodium content, serum cholesterol, and 24-h urinary hydroxylysine excretion, were consistent with euthyroidism. On the other hand, the mean pulse wave arrival time was significantly reduced, consistent with hyperthyroidism. Three control patients, 2 with Lowe's syndrome and 1 with benign cystinosis, had normal thyroid studies. Eight of the patients were given either exogenous L-T4 or T3 in doses which were increased at weekly intervals. The serum TSH concentrations were suppressed to normal only after elevation of serum levels of thyroid hormones and with high exogenous thyroid replacement doses. The data suggest abnormal pituitary resistance to feedback by thyroid hormone in patients with cystinosis. We believe this to be the first description of the association of a heritable metabolic disease with such pituitary resistance.

Child↗
PubMed1995

Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis.

Primary hypothyroidism is a known complication of nephropathic cystinosis, a lysosomal storage disorder characterized by renal failure as well as deterioration of other organs. The drug cysteamine depletes lysosomes of cystine and helps preserve renal function and enhance growth in cystinosis patients. To determine whether cysteamine also prevents hypothyroidism, we retrospectively divided 101 patients into group A (n = 28; well treated), group B (n = 26; partially treated), and group C (n = 47; poorly treated). Lifetable analysis indicated a significantly higher probability of remaining free of L-T4 replacement in group A vs. group B (P = 0.09) or group C (P = 0.004). Cysteamine therapy also improved mean height z-scores (-2.17 in group A, -3.04 in group B, and -4.07 in group C) and reduced the bone age deficit (i.e. chronological age minus bone age) by 1.5 yr for every 10 yr of previous cysteamine therapy. We conclude that in addition to its other salutary effects, oral cysteamine therapy helps prevent hypothyroidism and enhances growth in patients with nephropathic cystinosis.

Adolescent↗
PubMed2001

Characterization of a putative founder mutation that accounts for the high incidence of cystinosis in Brittany.

Cystinosis is an autosomal recessive disorder, characterized by an accumulation of intralysosomal cystine, with an incidence of 1 in 100,000 to 200,000 live births. A higher incidence of cystinosis, 1 in 26,000 live births, has been reported in the western French province of Brittany. PCR amplification and sequencing has identified a 27-bp deletion starting 3 bp before the end of exon 8 and continuing into intron 8, 898-900+24del27, which has only been detected in families from this region. Reverse transcription-PCR amplification of RNA from an affected individual has shown that this mutation is indeed a splice-site mutation and results in the production of aberrant transcripts. These transcripts are predicted to either severely truncate cystinosin or alter its topology, thus accounting for the severe phenotype of these individuals. The mutation 898-900+24del27 has been identified in 7 of 18 alleles studied. This mutation is likely to be a founder mutation and would account for the higher incidence of cystinosis in Brittany.(1)

Adolescent↗
PubMedDate not supplied

Evolution of ocular manifestations in nephropathic cystinosis: a long-term study of a population treated with cysteamine.

BACKGROUND: Nephropathic cystinosis is characterized by an accumulation of cystine crystals within most body tissues. Renal transplantation and oral cysteamine have improved the general prognosis of the disease, and ocular manifestations are now the most common complication. This long-term follow-up study describes the sequence of ocular manifestations in patients with nephropathic cystinosis treated with oral and topical cysteamine. METHODS: Data were recorded for all patients with cystinosis examined between 1980 and 2000. For each patient, photophobia and visual acuity were evaluated and slit-lamp and fundus examinations were performed. For some patients, an electroretinogram was also performed. RESULTS: Twenty-nine patients were observed during this period. They received oral and topical cysteamine. Photophobia and loss of visual acuity generally began by 10 years of age but were severe only after 15 years of age. Peripheral corneal epithelial infiltration appeared in the first few years of life. Infiltration evolved toward the depth and center of the cornea during the second decade of life. Retinopathy was present in 51.7% of the patients, with 3 cases of maculopathy and 3 cases of flattening on electroretinogram. CONCLUSIONS: Photophobia and corneal infiltration, although generally severe after 15 years of age, could be treated with topical cysteamine and corneal transplantation. Retinal infiltration, previously described as frequent and potentially blinding, is currently observed in only half of these patients, with mild visual impairment. This could be related to the treatment with oral cysteamine reaching the retinal vascularization.

Administration, Oral↗
PubMed2004

Keratopathy of multiple myeloma masquerading as corneal crystals of ocular cystinosis.

We describe a 49-year-old woman in whom ocular cystinosis was diagnosed on the basis of a routine eye examination 12 years previously. Conjunctival biopsy was reported to support the diagnosis. The patient described photophobia for the past 5 years and reported a 2-fold increase in her serum IgG level for the past 12 years. On ophthalmic examination, corneal crystals were evident in the epithelium and superficial stromal layers, rather than throughout the corneal epithelium and the entire stroma as in ocular cystinosis. The patient's serum protein level was elevated at 8.7 g/dL; protein electrophoresis showed an elevated gamma-globulin peak, and the IgG level was twice that of normal at 2820 mg/dL. Bone marrow biopsy confirmed the diagnosis of multiple myeloma. This case illustrates that multiple myeloma can mimic corneal findings of cystinosis.

Corneal Diseases↗