Parenchymal organ cystine depletion with long-term cysteamine therapy

doi:10.1016/0885-4505(92)90074-9

Biochemical Medicine and Metabolic Biology

Volume 48, Issue 3, December 1992, Pages 275-285

Biochemical Medicine...

https://doi.org/10.1016/0885-4505(92)90074-9 Get rights and content

Abstract

Nephropathic cystinosis is a lysosomal storage disorder characterized by renal failure, multisystem organ damage, and poor growth. Oral cysteamine therapy retards renal deterioration and enhances growth, but parenchymal organ cystine depletion has never been documented. We measured skeletal muscle cystine in 11 cystinosis patients not treated with cysteamine; analysis of their values plus 11 published values showed that muscle cystine increases linearly with age in cystinosis patients (slope, 0.074 nmol half-cystine/mg wet wt/year). In contrast, 15 patients treated for 4 to 11 years with oral cysteamine had a relatively constant muscle cystine content (slope, 0.004 nmol half-cystine/mg wet wt/year). The treated patients' mean muscle cystine, 0.091 ± 0.064 (SD) nmol half-cystine/mg wet wt, was significantly less (P < 0.001) than that for the 11 youngest untreated patients, 0.754 ± 0.534 nmol half-cystine/mg wet wt. On postmortem examination, a 9-year-old cystinosis patient treated for 8 years with oral cysteamine had liver, kidney, pancreas, lung, and spleen cystine values 5 to 90 times lower than those of an untreated age-matched control. We conclude that long-term oral cysteamine therapy routinely depletes cystinotic skeletal muscle of cystine; cysteamine is the treatment of choice for the prevention of both renal and nonrenal complications of cystinosis.

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Cited by (51)

Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis
2015, Nefrologia
Citation Excerpt :
Acute presentation: epilepsy, stroke, encephalopathy, cephalalgia54–57 Subacute/progressive presentation: intracranial hypertension, cerebral atrophy, ataxia, pyramidalism, gait disorders, basal and periventricular lymph node calcifications, demyelination of white matter, mental deterioration58–66 Neurocognitive alterations:67–73 in cystinotic patients, a specific profile of alterations in visual-motor integration, visual memory, maintained attention, planning, motor processing speed and arithmetic calculation have been described.
Cystinosis is a rare systemic lysosomal storage disease that mainly affects the kidney and the eye. Renal replacement therapy is started in patients with cystinosis during the first decade of life in the absence of treatment. The prognosis of cystinosis depends on early diagnosis and the prompt start of and good compliance with cysteamine treatment. Kidney disease progression, extra-renal complications and shorter life expectancy are more pronounced in patients who do not adhere to treatment.
The aim of this work was to establish recommendations for the comprehensive care of cystinosis and facilitate patient transition from paediatric to adult medicine, based on clinical experience. The goal is to reduce the impact of the disease and improve prognosis and patient quality of life.
Bibliographic research and consensus meetings with a multidisciplinary professional team of clinical experts in cystinosis (T-CiS.bcn group) from 5 hospitals in Barcelona.
This consensus document gathers specific recommendations for the diagnosis, treatment and multidisciplinary care of cystinotic patients in the following areas: nephrology, dialysis, kidney transplantation, ophthalmology, endocrinology, neurology, laboratory, genetic counselling, nursing and pharmacy.
Guidelines for the comprehensive care of cystinosis provide a support tool for health professionals who look after these patients. They are based on the following main pillars: (a) a multidisciplinary approach; (b) appropriate disease monitoring and control of white blood cell (WBC) cystine levels; (c) the importance of adherence to cysteamine treatment; and (d) the promotion of patient self-care by means of disease education programmes. All these recommendations will lead us, in a second phase, to create a coordinated model of transition from paediatric to adult care services which will cover the specific needs of cystinosis.
La cistinosis es una enfermedad lisosomal minoritaria de expresión sistémica con especial afectación renal y oftalmológica, en la que los pacientes inician terapia renal sustitutiva en la primera década de la vida en ausencia de tratamiento. El pronóstico de la cistinosis depende del diagnóstico precoz, la pronta instauración del tratamiento con cisteamina y el buen cumplimiento terapéutico. La progresión de la enfermedad renal y de las complicaciones extrarrenales y una menor supervivencia, son más acentuadas en pacientes no adherentes.
El objetivo de este trabajo fue la elaboración de unas recomendaciones para la atención integral de la cistinosis y la transición del adolescente a la medicina del adulto, basadas en la experiencia clínica, con el fin de reducir el impacto de la enfermedad y mejorar la calidad de vida y el pronóstico del paciente.
Búsqueda bibliográfica y reuniones de consenso de un equipo multidisciplinar de expertos en la práctica clínica con pacientes afectos de cistinosis (Grupo T-CiS.bcn), procedentes de 5 hospitales localizados en Barcelona.
El documento recoge recomendaciones específicas y necesarias para el diagnóstico, tratamiento y seguimiento multidisciplinar de la cistinosis en las siguientes áreas: nefrología, diálisis, trasplante renal, oftalmología, endocrinología, neurología, laboratorio, consejo genético, enfermería y farmacia.
Disponer de un documento de referencia para la atención integral de la cistinosis constituye una herramienta de soporte para los profesionales de la salud que asisten a estos pacientes. Los principales pilares en los que se sustenta son: a) el enfoque multidisciplinar, b) la adecuada monitorización de la enfermedad y control de los niveles de cistina intraleucocitarios, c) la importancia de la adherencia al tratamiento con cisteamina y d) la promoción del autocuidado del paciente mediante programas de educación en la enfermedad. Todo ello conducirá, en una segunda fase, a la elaboración de un modelo de transición coordinado entre los servicios de pediatría y de adultos que contemple las necesidades específicas de la cistinosis.
Cysteamine therapy: A treatment for cystinosis, not a cure
2012, Kidney International
Cystinosis as a clinical entity is a progressive dysfunction of multiple organs caused by the accumulation of cystine in the tissues, leading, for example, to end-stage renal failure, diabetes, hypothyroidism, myopathy, and central nervous system deterioration. Brodin-Sartorius and colleagues present a long-term study on the impact of cysteamine therapy on these complications. The data show that cysteamine improves the outcome and complications of cystinosis but does not prevent them.
Generation of the oxidized form protects human brain type creatine kinase against cystine-induced inactivation
2011, International Journal of Biological Macromolecules
Citation Excerpt :
Treatment initiated in the first two years of age could delay the evolution of this disease. Without treatment, most children with cystinosis develop renal failure, visuospatial difficulties, and increasing discrepancy in a progressive cognitive impairment due to cystine accumulation in the brain [4,5]. Accumulated data indicated that at the molecule level, the high concentration of intracellular cystine affected the activity and functions of many thiol-containing enzymes, such as pyruvate kinase and creatine kinase [6–9].
Cystine accumulation in cystinotic patients has been reported to inhibit brain type creatine kinase (BBCK), an important thiol-containing enzyme in energy homeostasis. In this research, we found that the oxidized form of BBCK (O-BBCK) was induced by cystine, and the intramolecular disulfide bond of O-BBCK was formed between Cys74 and Cys254. The wild type BBCK was found to be more resistant to the inactivation induced by cystine when compared to the single point mutant C74S or C254S. Meanwhile, the existence of GSH could protect the wild type BBCK more efficiently than the mutants. These observations suggested that the ability to generate the oxidized form could protect BBCK against the intracellular oxidative stress.
Cystine Inhibits Creatine Kinase Activity in Pig Retina
2007, Archives of Medical Research
Citation Excerpt :
In this case it is possible to envisage that a diminution of these enzyme activities may potentially impair energy metabolism, contributing to the tissue damage through programmed cell death. Considering that cysteamine is used to treat patients with cystinosis because it causes parenchymal organ cystine depletion (8), the present data provide another possible beneficial effect for the use of this drug because the protective effect of cysteamine could be important in preventing some metabolic consequences of cystine accumulation, such as inhibition of CK activity and possibly other thiol enzymes. However, further studies are necessary to evaluate the activity of CK and other thiol enzymes in patients affected with cystinosis.
Cystinosis is an autosomal recessive disorder associated with lysosomal cystine accumulation caused by defective cystine efflux. Visual deficit is a possible consequence of cystine accumulation in cornea and retina. Fibroblasts from cystinotic patients present ATP deficit with intact mitochondrial energy-generating capacity by an unknown mechanism. Considering that creatine kinase is a thiol enzyme crucial for energy homeostasis in retina, and disulfides like cystine may alter thiol enzymes, the main objective of the present study was to investigate the effect of cystine and cysteamine, the drug used for treatment of cystinotic patients, on creatine kinase activity in cytosolic and mitochondrial fractions of the retina from adult pigs.
Retina was isolated from 6-month-old Landrace pigs, homogenized and mitochondrial and cytosolic fractions separated by centrifugation. Cytosolic and mitochondrial creatine kinase activities were determined in the presence of different concentrations of cystine and/or cysteamine.
Cystine inhibited the enzyme activity in a dose- and time-dependent manner and cysteamine prevented and reversed the inhibition caused by cystine, suggesting that cystine inhibits creatine kinase activity by oxidation of the sulfhydryl groups of the enzyme.
Considering that creatine kinase is a crucial enzyme for retina energy homeostasis, in case cystine leaves lysosome these results provide a possible mechanism for cystine toxicity and also another beneficial effect for the use of cysteamine in patients with cystinosis.
Ophthalmic Manifestations and Histopathology of Infantile Nephropathic Cystinosis: Report of a Case and Review of the Literature
2007, Survey of Ophthalmology
Cystinosis is a rare autosomal recessive metabolic disorder characterized by the intracellular accumulation of cystine, the disulfide of the amino acid cysteine, in many organs and tissues. Infantile nephropathic cystinosis is the most severe phenotype. Corneal crystal accumulation and pigmentary retinopathy were originally the most commonly described ophthalmic manifestations, but successful kidney transplantation significantly changed the natural history of the disease. As cystinosis patients now live longer, long-term complications in extrarenal tissues, including the eye, have become apparent. A case of an adult patient with infantile nephropathic cystinosis is reported. He presented with many long-term ocular complications of cystinosis. After 4 years of follow-up, the patient died from sepsis. Pathology of the phthisical eyes demonstrated numerous electron-transparent polygonal spaces, bounded by single membrane, in corneal cells, retinal pigment epithelial cells, and even choroidal endothelial cells. The ophthalmic manifestations and pathology of infantile nephropathic cystinosis are discussed and reviewed in light of the current report and other cases in the literature.
Nephropathic Cystinosis. Posterior Segment Manifestations and Effects of Cysteamine Therapy
2006, Ophthalmology
Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by the intracellular accumulation of cystine. Treatment involves intracellular cystine depletion with oral cysteamine. A wide spectrum of ocular pathologic features has been associated with nephropathic cystinosis. We used the largest documented cohort of patients in the world to study the posterior segment manifestations associated with infantile nephropathic cystinosis and to determine retrospectively the effect of chronic oral cysteamine therapy on the frequency of these abnormalities.
Cross-sectional study of a series of patients.
Two hundred eight patients with infantile nephropathic cystinosis were studied at the National Institutes of Health between 1976 and 2004.
All patients underwent an ophthalmic evaluation. Patients older than 11 years also underwent Humphrey static perimetry, and electrophysiological testing was performed when possible.
Visual acuity, retina findings, visual fields, and electroretinographic (ERG) findings.
Pigmentary changes with retinal pigment epithelial mottling, seen as early as infancy, were the most common posterior segment manifestations. Moderate to severe constriction of the visual fields, as well as moderate to severe reduction of rod- and cone-mediated ERG responses, was seen in older patients. The frequency of retinopathy correlated directly with time not receiving oral cysteamine therapy and inversely with time receiving oral cysteamine therapy.
Infantile nephropathic cystinosis has posterior segment complications that can contribute to significant visual handicap. Early initiation of oral cysteamine therapy can reduce the frequency of posterior segment complications in cystinosis patients.

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Regular articleParenchymal organ cystine depletion with long-term cysteamine therapy

Abstract

Adv Pediatr

J Pediatr

J Pediatr

J Pediatr

J Biol Chem

Anal Biochem

Am J Med

J Pediatr

J Pediatr

J Biol Chem

J Biol Chem

J Pediatr

Lysosomal transport disorders: Cystinosis and sialic acid storage disorders

Lysosomal cystine transport is defective in cystinosis

Science

Complications of nephropathic cystinosis after renal failure

Pediatr Nephrol.

Pancreatic endocrine insufficiency in posttransplant cystinosis

Am J Dis Child

Neurologic complications in long-standing nephropathic cystinosis

Arch Neurol

Regular article
Parenchymal organ cystine depletion with long-term cysteamine therapy