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.     

Swallowing dysfunction in nephropathic cystinosis

BACKGROUND. Nephropathic cystinosis causes renal failure in most patients at approximately 10 years of age. This can be prevented or retarded by cystine-depleting therapy with oral cysteamine. Many patients who do not receive adequate cysteamine therapy undergo renal transplantation, but the accumulation of cystine continues in other organs, resulting in various clinical abnormalities. We report age-related swallowing dysfunction in patients with nephropathic cystinosis. METHODS. We studied 43 patients with cystinosis (24 who had received a renal transplant and 19 who had not), 3 to 31 years of age. Oral motor function was assessed by a cranial-nerve oral sensorimotor examination, and an oral motor index was calculated for each patient. The oral phase of swallowing was assessed by ultrasonography, and the pharyngeal and esophageal phases were evaluated by videofluoroscopy. RESULTS. Approximately half the patients were slow eaters. Oral motor dysfunction, reflected by a higher oral motor index, increased with age. Speech, oral structure and anatomy, and tongue and lip strength were particularly affected. Seven of nine patients 21 to 31 years old had abnormalities in all three phases of swallowing; the deficits were variable in younger patients. In 28 patients with cystinosis, the mean (+/- SD) duration of oropharyngeal swallowing for a dry swallow (3.06 +/- 1.06 seconds) was longer than in 14 normal subjects (1.89 +/- 0.57 seconds; P less than 0.001). This prolongation reflected impairment of the initiation phase of swallowing. CONCLUSIONS. Swallowing dysfunction is a late complication of nephropathic cystinosis, probably related to muscular dysfunction. Changes in the consistency of foods, swallowing exercises, and long-term cysteamine therapy should be considered for patients with cystinosis who have difficulty in swallowing.     

Cysteamine therapy for children with nephropathic cystinosis

We treated 93 children with nephropathic cystinosis with oral cysteamine (mean dose, 51.3 mg per kilogram of body weight per day) for up to 73 months. This agent is known to be effective in depleting cells of cystine. In our study, the mean cystine depletion from leukocytes was 82 percent. A historical control group of 55 children received either ascorbic acid (27 children) or placebo (28). At age six, 2 of 17 controls had a serum creatinine level less than 1.0 mg per deciliter, as compared with 17 of 27 patients treated with cysteamine for at least one year (odds ratio, 12.8; 95 percent confidence interval, 2.1 to 33.9). At the end of the study, creatinine clearance was higher in the cysteamine group than in the control group (38.5 vs. 29.7 ml per minute per 1.73 m2; 95 percent confidence limits on the difference, 1.8 and 15.8), even though the cysteamine group was on average 1.4 years older than the control group. Cysteamine also improved growth; those in the cysteamine group between two and three years of age grew at 93 percent of the normal velocity, as compared with 54 percent in the control group. Fourteen percent of the patients could not tolerate the taste and smell of cysteamine. Concurrent controls treated in a blinded fashion with a placebo were not included in this study. With this limitation in mind, we conclude that oral cysteamine, by depleting cells of cystine, helps maintain renal glomerular function, improves growth, and constitutes the current treatment of choice for nephropathic cystinosis.     

Clinical and molecular aspects of nephropathic cystinosis

 Nephropathic cystinosis, an autosomal recessively inherited lysosomal storage disease, results from impaired transport of the disulfide amino acid cystine out of cellular lysosomes. The consequent accumulation and crystallization of cystine destroys tissues, causing growth retardation in infancy, renal failure at 10 years of age, and a variety of other complications. Early oral therapy with the cystine-depleting agent cysteamine prevents renal deterioration and enhances growth. Although the lysosomal cystine carrier has been extensively studied, its molecular structure remains unknown. The lysosomal cystine transporter gene has been mapped by linkage analysis to human chromosome 17p between polymorphic microsatellite markers D17S1583 and D17S1584. Pertinent recombination events and homozygosity by descent has verified that the cystinosis gene lies in the 3.6 cM genetic interval between these two markers. The cystinosis region has been substantially reduced in size by the observation of recombination events in cystinosis patients between markers D17S1828 and D17S2167. According to radiation hybrid analysis, these two markers are separated by 10.2 cR₈₀₀₀ (centirad using 8000 rad radiation hybrids). Estimates of the physical size of this interval range from 187 to 510 kb. Four yeast artificial chromosomes have been identified which form a contig covering the original cystinosis region. Two P1 clones together may span the new, smaller interval, meaning that the cystinosis gene would lie on one of them. Current efforts are being directed toward using these P1 clones to isolate candidate cDNAs by a variety of methods. The ultimate cloning of the cystinosis gene will reveal how functional lysosomal porters are synthesized, targeted, processed, and integrated into the lysosomal membrane. Received: 18 April 1997 / Accepted: 2 July 1997     

Intra-leukocyte cystine in cystinosis treated with cysteamine]

Data on cystine leukocyte content are analyzed in cystinotic patients receiving cysteamine as a depleting agent of cellular cystine. During 2 years, 63 measurements of cystine leucocyte content were performed in 15 cystinotic patients, aged 20 months to 22 years, taking daily 40 to 65 mg/kg of cysteamine. An original method was used to measure leukocyte cystine: a binding protein assay with a specific cystine-binding protein from E. coli. Results were taken individually because of various clinical situations in patients. In 8 patients taking cysteamine regularly, 6 hours after a dose, cystine leukocyte content was between 1 and 2 nmol 1/2 cystine/mg protein, about 10 times less than basal values without treatment and 5 to 10 times more than control subjects. In less compliant patients, cystine leukocyte content was close to basal values without treatment (3 to 25 nmol/mg). Some variability was observed between individuals receiving cysteamine: pharmacokinetic parameters may need further investigation. This sensitive and specific assay helped in controlling compliance and adjusting dosage regimen in each patient. The aim was to maintain a minimum effective dosage in order to avoid toxic side effects of cysteamine.     

Cognition in nephropathic cystinosis: pattern of expression in heterozygous carriers

Individuals with cystinosis exhibit specific cognitive deficits in visual spatial function. The purpose of the current study was to examine if obligate heterozygotes of the CTNS mutation have the same pattern of cognitive functioning seen in homozygotes, namely aberrant visual-spatial functioning against a background of relatively intact visual-perceptual functioning and overall cognitive ability. Study participants were 254 adults (100 heterozygotes and 154 controls), ages 17 years 10 months through 74 years 9 months. Tests of intelligence, visual perceptual, and visual spatial functioning were administered. Our results showed that cystinosis heterozygotes demonstrated intelligence within the normal range, and performed similarly to controls on tests of visual-perceptual ability. In contrast, the heterozygotes performed significantly more poorly on each of the visual-spatial tests when compared to controls. Obligate heterozygotes for the CTNS mutation display a similar pattern of visual processing decrements as do individuals with cystinosis. Namely, carriers demonstrate relative weaknesses in visual-spatial processing, while maintaining normal visual perceptual ability and intelligence in the normal range. The visual spatial decrements in heterozygotes were not as marked as those found in individuals with cystinosis, suggesting a gene dosing effect. This study provides an impetus for other studies of gene-behavior relationships in recessive disorders, and may stimulate further interest in the role of aberrant genes on "individual differences" in behavior.     

Ineffectiveness of ascorbic acid therapy in nephropathic cystinosis.

Because high concentrations of ascorbic acid (0.57 mM) lower the free (nonprotein) cystine content of cultured cystinotic skin fibroblasts by over 50 per cent, we did a double-blind clinical trial to establish whether this drug would benefit cystinotic children. Sixty-four patients were randomized into the study; 32 received ascorbic acid (200 mg per kilogram of body weight per day), and 32 placebo. The study was terminated after approximately two years because there was no indication that vitamin C was beneficial and accumulating evidence that it might be harmful. Of 11 patients who left the study because of death or the requirement for dialysis or renal transplantation, eight were receiving ascorbic acid. The estimated relative risk (treatment vs. control) of an adverse event was R = 2.7, with a 90 per cent confidence interval of (0.8, 11.5). The serum creatinine concentration increased 0.53 mg per deciliter per year in patients receiving vitamin C and 0.24 mg per deciliter per year in patients receiving placebo (P = 0.08).     

Maternal uniparental heterodisomy of chromosome 17 in a patient with nephropathic cystinosis

We report maternal uniparental disomy of chromosome 17 (mat UPD17) in a 2.5-year-old girl presenting infantile cystinosis. This patient was homozygous for the 57 kb deletion encompassing the CTNS gene, frequently found in patients from the European origin. The proband''s mother was heterozygous for the deletion and the father did not carry the deletion. We carried out haplotype analysis with polymorphic markers spanning the whole chromosome 17. Informative markers showed the presence of two maternal alleles but no paternal allele for regions spanning the 17q arm and the proximal half of 17p, and only one maternal allele on the distal 17p arm. As deletion of half of 17p is probably not viable, these results suggest mat UPD17 with heterodisomy of 17q and proximal 17p and isodisomy of distal 17p. This is the first demonstration of mat UPD17, in particular of isodisomy 17p, in cystinosis.     

The incidence of atubular glomeruli in nephropathic cystinosis renal biopsies

Nephropathic cystinosis results from lysosomal cystine storage and, if untreated with cysteamine, results in end-stage renal disease by 10 years of age. The renal Fanconi syndrome occurs in the first year of life and is accompanied by a characteristic “swan neck” deformity of the proximal renal tubule. The linkage between cystine storage, Fanconi syndrome, and renal failure has not been understood. This study reports the presence of substantial numbers of atubular glomeruli (ATG) in end-stage cystinotic renal tissue. Compared to normal renal tissue, cystinotic kidneys at end stage had 69% atubular glomeruli and 30% atrophic glomeruli. Normal renal tissue had 4% ATG and 0% atrophic glomeruli (p < 0.0001 for both comparisons). These nonfunctioning nephrons may be the end result of cell loss from the tubules and represent the final stage of the swan neck deformity. The process is consistent with the previously reported increased apoptosis in renal tubule cells due to lysosomal cystine storage.     

High cystine in platelets from patients with nephropathic cystinosis: a chemical, ultrastructural, and functional evaluation

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.     

Halitosis in cystinosis patients after administration of immediate-release cysteamine bitartrate compared to delayed-release cysteamine bitartrate

Halitosis due to dimethylsulfide (DMS) generation is a major side effect of cysteamine in the treatment of cystinosis. Recently, an enteric coated formulation of cysteamine bitartrate (RP103) administered twice daily was demonstrated to be non-inferior for lowering WBC cystine levels compared to the non-enteric coated formulation (Cystagon?), administered 4 times per day. Since both formulations had different pharmacokinetic profiles, we compared DMS breath levels after administration of either RP103 or Cystagon? in four cystinosis patients. Although cysteamine areas under the curve (AUCs) were comparable, AUC of DMS was lower after the administration of RP103 compared to Cystagon?. This observation is of importance in cystinosis patients, since halitosis hampers compliance with cysteamine therapy.     

Corneal and conjunctival crystals in paraproteinemia

A 64-year-old woman with bilateral corneal and conjunctival crystal deposition was evaluated. A biopsy of her conjunctiva showed intracytoplasmic inclusions of immunoglobulin crystals in fibrocytes, macrophages, and endothelial cells. Serum protein electrophoresis showed elevated kappa and IgA light and heavy chains which corresponded with immunoperoxidase staining results of the conjunctival biopsy. Conjunctival and corneal crystal deposition may be indicative of paraproteinemia, and histopathologic examination of a conjunctival biopsy may be useful in diagnosing this condition.     

Hepatitis C: natural history, biology, treatment monitoring

This article presents the laboratory tests used to diagnose hepatitis C, to evaluate the severity of the chronic fibrosing disease, and to monitor the efficacy of treatment. Histological examination of liver biopsies is of the utmost importance for evaluating the development of fibrosis. Factors that precipitate fibrosis are reviewed. The annual rate of fibrosis progression can be assessed based on the estimated duration of hepatitis C virus contamination and on the fibrosis score established using the METAVIR classification. This allows to distinguish slow, fast, and intermediate fibrosis and to estimate the mean time to cirrhosis development. Combined use of interferon alpha (3 million units three times a week) and of Ribavirine (1000-1200 mg per day orally according to body weight) for 6 to 12 months is currently the standard treatment for hepatitis C. Treatment efficacy varies with a number of virus-related factors (genotype, viral burden) and patient-related factor (hepatic fibrosis, age, sex). In nonresponders, the value of treatment should not be assessed in terms of efficacy but in terms of slowing of fibrosis progression.     

Multicystic peritoneal mesothelioma in an octogenarian: diagnosis, natural history, and treatment

Multicystic peritoneal mesothelioma (MCPM) is a rare cystic proliferation most often seen in women of reproductive age with a history of prior abdominal surgery. This is a case report of an 83-year-old woman diagnosed with MCPM during an exploratory laparotomy for presumed peritoneal carcinomatosis from colon cancer. After complete removal of all visible MCPM, the patient remains free of both colon cancer and MCPM. This article reviews the literature with regards to the pathology, natural history, risk of malignant transformation, and current options for management of MCPM, including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.     

Gastric intestinal metaplasia: subtypes and natural history

BACKGROUND: It has been suggested that the subtyping of intestinal metaplasia in the stomach is useful in stratifying patients with regard to risk of developing gastric cancer. AIM: To determine whether subtyping intestinal metaplasia provided useful information regarding the natural history of intestinal metaplasia. METHODS: The study used large cup gastric biopsy specimens from predetermined locations (gastric mapping). Follow up biopsies were obtained at one, two, and/or nine years. Biopsies with intestinal metaplasia were stained with high iron diamine/Alcian blue (HID/AB) to determine whether they expressed neutral mucins, sialomucins, or sulphomucins. RESULTS: Seventy nine patients with intestinal metaplasia were studied and characterised with regard to the most advanced subtype of intestinal metaplasia. The most severe type of intestinal metaplasia was type II in 33 patients and type III in 34 patients. Helicobacter pylori was cured in 67 patients. Follow up showed that changes in type of metaplasia (apparent regression or progression) occurred in both directions and were independent of H pylori status. For example, biopsy sites with "loss" of metaplasia at a follow up visit might have it "reappear" at a subsequent visit. During follow up, no patient developed gastric dysplasia or died from gastric cancer. CONCLUSION: HID subtyping did not provide useful information to the clinician or the pathologist. The data are consistent with the notion that the pattern, extent, and severity of atrophy with/without intestinal metaplasia is a far more important predictor of increased cancer risk than intestinal metaplasia subtype.     

Carpenter syndrome: natural history and clinical spectrum

Recently, we evaluated three sibs with Carpenter syndrome, permitting further clinical, orthopedic, radiographic, and psychometric delineation of this disorder. All three patients were operated on for craniostenosis at or before 2 months. Although all had gross motor delay in early infancy, two had normal intelligence at 12 months and 10 years, respectively. Bony abnormalities contributed to functional impairment especially in the older children. Preaxial polydactyly of feet was present in all three affected sibs and in all other reported individuals with this condition, allowing differentiation of Carpenter syndrome from the other autosomal-recessive acrocephalopolysyndactyly syndromes.