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PubMed1988

NIH conference. Cystinosis: progress in a prototypic disease.

OBJECTIVE: To review the history, basic defect, pathogenesis, clinical manifestations, diagnosis, and treatment of nephropathic cystinosis. DESIGN: Lysosomal membrane transport studies, clinical reports, and a historically controlled 7-year trial of oral cysteamine therapy. SETTING: University centers in the United States and Canada. PATIENTS: One hundred forty-eight children, aged 0 to 12, with nephropathic cystinosis before renal transplant, who had renal tubular Fanconi syndrome, failure to grow, corneal cystine crystals, and elevated leukocyte cystine; 34 patients, aged 9 to 29, after transplant, some with visual impairment, corneal erosions, pancreatic dysfunction, or neurologic deterioration. INTERVENTION: Before transplant, replacement of renal losses, and treatment with oral cysteamine (55 mg/kg body weight.d for 1 to 6 years) and topical cysteamine eyedrops (0.1%, 1 drop/h while awake, for 6 months). After transplant, oral cysteamine and symptomatic treatment of late complications. MEASUREMENTS AND MAIN RESULTS: Untreated patients reached renal failure at age 10. Oral cysteamine lowered leukocyte cystine over 80%, and in patients before transplant, improved growth and preserved renal function (mean creatinine clearance [+/- SE], 0.64 +/- 0.04 mL/s.1.73 m2 [38.5 +/- 2.5 mL/min.1.73 m2] in the cysteamine group compared with 0.50 +/- 0.03 mL/s.1.73 m2 [29.7 +/- 2.0 mL/min.1.73 m2] in controls; 95% CI for the difference, 1.8 to 15.8). Cysteamine eyedrops cleared the corneal crystals of two children less than 2 years old. CONCLUSIONS: Cystinosis is a lysosomal storage disease due to impaired transport of cystine out of lysosomes. In young children, growth can be improved and renal deterioration delayed or prevented by oral cysteamine. Nonrenal complications after transplant might be prevented with long-term oral cysteamine.

Adolescent↗
PubMed2000

[Cystinosis from childhood to adulthood].

Nephropathic cystinosis is a metabolic disease related to lysosomal cystine accumulation in almost all tissues of the body. The first symptoms set up from 5 or 6 months of age including anorexia vomiting polyurodipsia and failure to thrive associated with a proximal tubulopathy (glycosuria, tubular proteinuria, loss of bicarbonate, potassium, phosphorus, etc.) Treatment by cysteamine dramatically changed the prognostic. If started early this treatment allows to delay and possibly to prevent the spontaneous evolution towards end stage renal disease between 6 and 12 years of age and to avoid the growth failure. On the long term the disease involves other organs: eyes, thyroid endocrine pancreas, muscle and central nervous system. The diagnosis of cystinosis is based on the cystine leukocyte assay allowing also the follow up and the adjustment of the treatment. Prenatal diagnosis is possible on chorionic sample. The gene of this recessive disease, mapping on chromosome 17 was recently identified. This gene encodes a protein of the lysosomal membrane involved in the transport of cystine out of the lysosome. There is a juvenile, late onset, form of cystinosis its main symptom is proteinuria with variable tubular alterations. The so called adult form is asymptomatic its only symptom is corneal deposits most often found by chance examination.

Adult↗
PubMed1992

[Ocular manifestations in a case of infantile cystinosis].

A case of infantile cystinosis was reported. The diagnosis of cystinosis was made by the renal Fanconi syndrome and the ocular findings. The patient showed typical corneal and fundus changes associated with cystinosis. Corneal crystals and fundus pigmentary change were found early in life. The deposition of corneal crystals increased in the course of the disease, especially in the nasal and the temporal sides close to the limbus. By specular microscopy, the corneal crystals were needle-shaped and were larger and more numerous in the superficial layer of the stroma. The same shape of crystals ere found in the corneal endothelium, and the size of endothelial cells was markedly increased. There were also small crystals on the surface of the iris. The entire fundus showed a mottled appearance characterized by mixture of fine granular pigmentation and depigmentation associated with patchy depigmentation in the periphery. On the anterior surface of the retina, a glistening crystal appeared. As the crystal deposition in ocular tissues increases, even after successful peritoneal dialysis, eventual impairment of visual function may be expected.

Crystallization↗
PubMed2004

[From gene to disease: cystinosis].

Cystinosis is an autosomal recessive disorder caused by an impaired transport of cystine out of lysosomes. The most severe infantile form of cystinosis starts with Fanconi syndrome at the age of 3-6 months. Untreated patients develop renal failure before the age of 10. The cystinosis gene (CTNS) maps to chromosome 17p13, spans 23 kb and is composed of 12 exons. CTNS encodes a 367 amino acid protein, cystinosin, which is a H(+)-driven lysosomal cystine transporter. It is enigmatic how lysosomal cystine accumulation induces the clinical symptoms. ATP depletion was demonstrated in an experimental model consisting of loading lysosomes with cystine dimethylester. The amino-thiol cysteamine depletes lysosomal cystine content by a disulfide-exchange reaction with cystine. Therapy with cysteamine should be administered as early as possible and continued after a renal transplantation as the extra renal damage still progresses. Improved life expectancy of cystinotic patients requires the attention of internists with a special interest for this rare disorder.

Amino Acid Transport Systems, Neutral↗
PubMedDate not supplied

[Cystinosis: an infrequent cause of distal myopathy].

INTRODUCTION: Cystinosis is a hereditary disease with clinical symptoms that are caused by the accumulation of cystine crystals in different tissues. Distal vacuolar myopathy has been reported as one of its later complications. CASE REPORT: Here, we present the case of a 20-year-old male diagnosed with cystinosis at the age of 2 years, with severe renal involvement that required a transplant. The patient gradually developed weakness and atrophy of the muscles in his hands. Neurophysiological and histological studies enabled a diagnosis of distal vacuolar myopathy to be established, and electron microscopy revealed deposits of cystine crystals. CONCLUSIONS: Cystinosis must be included within the differential diagnosis of distal myopathies. Timely treatment with cysteamine could prevent the development of this complication.

Adult↗
PubMed2005

Ocular manifestations in adolescent cystinosis: case report in Thailand.

Three siblings with a family history of consanguinity presented with short stature and two of the patients had leg deformity. None of them experienced ocular or renal symptoms at presentation. After the pediatricians found characteristics of Fanconi syndrome, an ophthalmic consultation was requested Ocular examination revealed typical cystine crystals deposited in the cornea and conjunctivae. No crystal deposits were found elsewhere in the eyes. Fundoscopic examination was normal. Two patients who underwent a complete ocular examination were diagnosed as adolescent cystinosis. The youngest patient who lost to follow up before completed ocular examination was suspected for adolescent cystinosis. This is the first report of cystinosis with ocular manifestation from Thailand.

Adolescent↗
PubMed1991

Acquired structural genitourinary abnormalities contributing to deterioration of renal function in older patients with nephropathic cystinosis.

The natural progression of nephropathic cystinosis to end stage renal disease can be delayed, sometimes by many years, by the reducing agent, cysteamine, which lowers intracellular cystine content to near normal. We report on two patients with nephropathic cystinosis who were treated with cysteamine and developed structural genitourinary abnormalities which may have contributed to an increase in the rate of decline of renal function. One patient, aged 11 years, was found to have massive megacystis and hydroureteronephrosis but no anatomic bladder outlet obstruction. His abnormality was presumed to be related to chronic high urine volumes leading to megacystis and physiologic ureteral obstruction. Vesicostomy stabilized renal function. The second patient, aged 11 1/2 years, was found to have bilateral renal cystic disease which presumably was acquired and may have been related to long-standing hypokalemia. Minor renal abnormalities were found by ultrasound in five additional cystinotic children. We concluded that older children with nephropathic cystinosis may be prone to acquire structural abnormalities of their kidneys or urinary tract.

Creatinine↗
PubMed1979

[Adolescent cystinosis. Review of the literature and case report (author's transl)].

A case of adolescent cystinosis in a 17 1/2 year-old boy is reported. The metabolic disorder was diagnosed at the age of 13 years. Cystine was demonstrated in cornea and bone marrow and was increased in fibroblasts (3.64 nMol 1/2-cystine/mg protein). The renal lesions were characteristic of mesangioproliferative glomerulonephritis. The rate of detoriation in renal function increased from 1.5 to 6.6 mg/100 ml serum creatinine during the time of follow up. As well as the parents one brother (0.51 nMol 1/2-cystine/mg protein) appears to be a heterozygote carrier of the cystinosis gene. The striking features in adolescent cystinosis were shown by a review of the literature and the present case report.

Adolescent↗
PubMed1984

Nephropathic cystinosis in black children. Case reports.

Cystinosis is thought to be rare in Black patients. Two cases of nephropathic cystinosis in Blacks in early childhood are reported. One patient presented with classic features of Fanconi's syndrome with failure to thrive and rickets, while the other had polyuria, growth failure and rickets. This article highlights the need for the exclusion of cystinosis in any Black patient presenting with Fanconi's syndrome.

Acidosis, Renal Tubular↗
PubMed1980

[Continuous enteral feeding in pediatric nephrology. Long-term results in children with congenital nephrotic syndrome, severe cystinosis and renal failure (author's transl)].

This is the report of the results obtained with continuous enteral feeding in congenital nephrotic syndrome (3 cases), cystinosis (3 cases) and renal failure (3 cases). Ages of patients at the beginning of treatment ranged from 10 days to 3 years. Enteral nutrition was given for periods ranging from 4 to 37 months; mean energetic intake was 116% of the levels recommended according to developmental age and protein diets were 138%; 115% and 84% of the recommended amounts in nephrotic syndromes, cystinosis and renal failure, respectively. This treatment obtained the survival of most patients. In congenital nephrotic syndromes, growth improved clearly with acceleration of the curve and restoration of plasma albumin level. In cystinosis, a better fluid and electrolyte balance was obtained and growth curve sometimes improved in a spectacular fashion. Finally, in renal failure, effect on growth was favourable in 2 cases and nil in the third: these findings show that normalization of energetic intakes does not induce normal growth in children with uremia.

Child, Preschool↗
PubMed1993

Classic nephropathic cystinosis as an adult disease.

OBJECTIVE: To delineate the clinical characteristics of infantile nephropathic cystinosis in adult patients who have undergone renal transplantation. DESIGN: Case series. SETTING: Clinical research unit. PATIENTS: All 36 adult patients with nephropathic cystinosis referred to the National Institutes of Health. OUTCOME MEASURES: Longevity, growth, renal allograft survival, visual acuity, endocrine insufficiency, myopathy and swallowing dysfunction, cerebral calcifications, and occupational status. RESULTS: Of the 36 patients, seven were dead, five with functioning allografts. The 1-year and 5-year graft survival rates for 30 cadaveric allografts were 90% and 75%, respectively. The patients' mean height and weight were severely retarded. Five patients were legally blind, and three others had severely impaired vision in one eye. Thirty-one (86%) of 36 patients required thyroid hormone replacement therapy. One third had a distal myopathy, and 21 had moderate to severe swallowing abnormalities. Eight patients had cerebral calcifications on computed tomographic scan. Despite these complications, the sighted patients engaged in a normal variety of occupations. Only 11 patients were receiving adequate cystine-depleting therapy with cysteamine (mercaptamine) or phosphocysteamine. CONCLUSIONS: Adult patients with nephropathic cystinosis suffer serious complications of the disease.

Adult↗
PubMed1998

Myopathy in two siblings with nephropathic cystinosis.

Nephropathic cystinosis is a hereditary disorder characterized by a specific defect in the transport of cystine across the lysosomal membrane, leading to an accumulation of protein-free cystine in tissues, including conjunctiva, liver, bone marrow and kidney. Renal transplantation is necessary because of renal failure. With improved life-expectancy, neurological complications have been reported, including cases of distal myopathy diagnosed ante- and post-mortem. We report on two further rare cases of two siblings suffering from cystinosis who developed a predominantly distal myopathy, proven electrophysiologically and on biopsy during life. The reported clinical picture of a distal atrophy resembling a neurogenic disease, confirms a picture apparently typical in cystinosis. Possible effects of cysteamine therapy on the course of the myopathy are discussed. Copyright 1998 Lippincott Williams & Wilkins

Journal Article↗
PubMed2000

Identification and characterisation of the murine homologue of the gene responsible for cystinosis, Ctns.

BACKGROUND: Cystinosis is an autosomal recessive disorder characterised by an intralysosomal accumulation of cystine, and affected individuals progress to end-stage renal failure before the age of ten. The causative gene, CTNS, was cloned in 1998 and the encoded protein, cystinosin, was predicted to be a lysosomal membrane protein. RESULTS: We have cloned the murine homologue of CTNS, Ctns, and the encoded amino acid sequence is 92.6% similar to cystinosin. We localised Ctns to mouse chromosome 11 in a region syntenic to human chromosome 17 containing CTNS. Ctns is widely expressed in all tissues tested with the exception of skeletal muscle, in contrast to CTNS. CONCLUSIONS: We have isolated, characterised and localised Ctns, the murine homologue of CTNS underlying cystinosis. Furthermore, our work has brought to light the existence of a differential pattern of expression between the human and murine homologues, providing critical information for the generation of a mouse model for cystinosis.

Journal Article↗
PubMed1991

Neurophysiologic studies of the peripheral nervous system in nephropathic cystinosis.

Cystinosis is an autosomal recessive metabolic disorder in which nonprotein cystine accumulates within most body tissues due to a defect in lysosomal cystine transport. Neurologic declarations are only recently being recognized. We studied 13 cystinotic subjects (aged 5 to 21 years old), determining median motor and sensory nerve conduction velocities, F waves, peroneal motor nerve conduction velocities, sural sensory nerve conduction velocities, median sympathetic skin response, electrocardiogram R-to-R variability, and blink reflex analysis. The results were normal. We conclude that neurophysiologic testing suggests relative sparing of the peripheral nervous system in nephropathic cystinosis.

Adolescent↗
PubMed1990

A randomized placebo-controlled trial of cysteamine eye drops in nephropathic cystinosis.

Eighteen patients with nephropathic cystinosis who were younger than 42 months and 11 patients 4 to 31 years of age were entered into a double-masked, randomized, placebo-controlled trial of topical cysteamine eye drops between November 1985 and September 1989. Eight of the younger patients and 2 of the older patients showed marked clearing of corneal crystals in one eye compared with the fellow eye. When the code was broken, all 10 patients were found to have received cysteamine eye drops in the improved eye. Of the remaining 19 patients 4 were unavailable for follow-up. In 15 patients no marked difference was noted between the two eyes. Eight have presumably been in the protocol for too short a time and several have been poor compliers with the therapy. These results not only demonstrate the potential for primary prevention of corneal crystal deposition but also, for the first time, offer the possibility of reversing the corneal complications of cystinosis in older patients.

Adolescent↗
PubMed1987

Prenatal diagnosis of cystinosis utilizing chorionic villus sampling.

The prenatal diagnosis of cystinosis is currently based on the increased amount of free-cystine present in amniotic fluid cells. Amniocyte cultures must be grown for at least 2 weeks to obtain sufficient cells for such measurements. Thus, the diagnosis cannot be made until close to 20 weeks gestational age by this method. We report a case in which chorionic villi were used for direct cystine measurement resulting in the in utero diagnosis of cystinosis at 9 weeks gestational age. The diagnosis was confirmed by the study of cultured chorionic villus cells, and of the 10-week abortus.

Chorionic Villi↗
PubMed1995

Cystinosis.

Nephropathic cystinosis is an autosomal recessive inborn error of metabolism characterized by the lysosomal storage of the disulphide amino acid cystine. It produces a variety of clinical manifestations including failure to thrive, the renal Fanconi syndrome, eye findings, and end-stage renal disease. A variety of phenotypes are known; however, the molecular defect underlying any of the forms has not yet been identified. Therapy of cystinosis with cysteamine averts the otherwise inevitable renal failure, but systemic therapy does not improve the corneal keratopathy. A number of presentations in this review detail approaches to gene identification, systemic therapy with cysteamine, measurement of cystine, and pathophysiological effects at the cellular and clinical level.

Cystinosis↗
PubMed1987

Complications of nephropathic cystinosis after renal failure.

Fifteen patients with nephropathic cystinosis, ranging in age from 13 to 27 years, were studied. Two were in renal failure; 13 had functioning renal allografts; 5 had severe, uncorrectable loss of visual acuity as well as posterior synechiae and crystal deposits on the lens surface. All 15 patients had photophobia and corneal erosions to variable degrees. All patients were growth retarded with delayed bone ages. Puberty occurred late, but was generally complete by 17 years of age. Hepatic function appeared normal. Only 1 patient had neurological deterioration, but 11 patients had some degree of cerebral atrophy radiologically. The continued accumulation of cystine within cystinotic tissues results in serious extrarenal complications many years after renal transplantation in cystinosis.

Adult↗