42 Cystinosis

Michel Broyer

42.1 Infantile Cystinosis – 533 42.1.1 Clinical Presentation – 533 42.1.2 Metabolic Derangement – 534 42.1.3 Genetics – 535 42.1.4 Diagnostic Tests – 535 42.1.5 Treatment – 535

42.2 Adolescent Cystinosis – 536

42.3 Adult Benign Cystinosis – 536

References – 536 532 Chapter 42 · Cystinosis

Lysosomal Porters for Cystine and Related Compounds Intralysosomal cystine is formed by protein catabolism lysosome and combine with cystine. This results in the in the organelle, and is normally exported by a cystine formation of cysteine (which can be exported by the porter (. Fig. 42.1) which contains a membrane protein, cysteine porter), and of the mixed disulfide, cysteine- cystinosin. Defects of this protein cause lysosomal ac- cysteamine (which, due to its structural analogy, can cumulation of cystine. Cysteamine can enter into the be exported by the lysine porter).

. Fig. 42.1. Lysosomal export of cystine and related compounds X 533 42 42.1 · Infantile Cystinosis

be life-threatening. Episodes of fever, probably related to Cystinosis is a generalized lysosomal storage disease dehydration, are also commonly noted. Lithiasis has been classified into three clinical phenotypes, of which the reported in rare cases, related to the high urinary excretion nephropathic or infantile form is by far the most fre- of urate, calcium and organic acids, and nephrocalcinosis quent. The first symptoms start at about 6 months of may be observed [2]. Blond hair and a fair complexion with age with anorexia, polyuria, failure to thrive and are difficult tanning after exposure to the sun are often noted manifestations of a Fanconi proximal renal tubulopathy. in white Caucasian cystinotic children. The natural history is that of end stage renal disease Involvement of the eye is a primary symptom of cysti- between 6 and 12 years. Survival beyond this age is as- nosis, starting with photophobia, which usually appears sociated with the development of extrarenal complica- at 2 or 3 years of age. Ophthalmological examination with tions in eyes, thyroid, gonads, endocrine pancreas, a slit lamp and a biomicroscope reveals cystine crystal de- muscle and central nervous system. An intermediate or posits. There are also fundal abnormalities with typical juvenile onset form, and a benign or adult form limited retinopathy and subsequent alterations of the retinogram to the eyes, are caused by lesions of the same gene. which usually appear later. The lysosomal cystine accumulation leads to cellular dysfunction of many organs without a clear mecha- End Stage Renal Failure nism. The disease is caused by mutations in the CTNS The natural history of the disease includes severe stunting gene coding for cystinosin, a lysosomal carrier protein. of growth and a progressive decrease of the glomerular fil- The diagnosis is ascertained by measurement of cystine tration rate, leading to end stage renal failure (ESRF) be- in leukocytes. Treatment is both supportive and spe- tween 6 and 12 years of age. The pathological basis is a dra- cific, the latter based on cysteamine, which effectively matic atrophy of the kidneys with glomerular sclerosis and decreases cystine accumulation. tubulo-interstitial fibrosis. Early onset of renal failure with- out marked Fanconi syndrome has been reported [3]. This evolution may be delayed by cysteamine treatment espe- cially when started in the first months of life. This treatment 42.1 Infantile Cystinosis also improves growth velocity. During the course of renal deterioration, the decrease in glomerular filtration is re- 42.1.1 Clinical Presentation flected by an improvement of urinary losses and a spurious regression of the Fanconi syndrome. In ESRF severe renal First Stage hypertension may develop. Repeat nasal bleeding is some- The first 3–6 months of life are usually symptom-free. The times observed in cystinotic patients on dialysis [4]. After first symptoms mostly develop before the age of 1 year [1]. kidney transplantation there is no recurrence of the Fan- They include feeding difficulties, anorexia, vomiting, polyu- coni syndrome even if cystine crystals are seen in the graft, ria, constipation and failure to thrive. If the diagnosis is de- where they are located inside macrophages or leukocytes. layed, severe rickets develops after 10-18 months in spite of When found, tubular symptoms in grafted patients are due correct vitamin D supplementation. Due to a severe concen- to a rejection reaction. trating defect a polyuria of 2-5 liters/day develops rapidly. Urine from cystinotic patients is characteristic, being pale Late Symptoms and cloudy with a peculiar odour, probably due to ami- The advent of renal replacement therapy and transplanta- noaciduria, and the diagnosis can be immediately suspected tion has uncovered the continued cystine accumulation in if both glucose and protein are found. When the disease has extrarenal organs and has emphasized the multisystemic become symptomatic, the full expression of the Fanconi nature of cystinosis, which may additionally involve the syndrome is generally present at first examination. It in- eyes, thyroid, liver, spleen, pancreas muscle and central cludes normoglycemic glycosuria, generalized aminoaci- nervous system (CNS) [4–7]. duria, tubular proteinuria (with massive excretion of E2-mi- croglobulin and lysozyme), decreased reabsorption of phos- Late Ocular Complications phate with hypophosphatemia, excessive losses of potassium The severity of eye involvement differs from one patient to and sodium bicarbonate leading to hypokalemia, hy- another [8]. Corneal deposits accumulate progressively in ponatremia and metabolic acidosis. Hypercalciuria is also the stroma of the cornea and iris in all patients and on the massive and hypouricemia is constant. Tubular loss of car- surface of the anterior lens and retina in some. Photopho- nitine may cause carnitine depletion. Kidney biopsy shows bia, watering and blepharospasm may become disabling; tubular abnormalities and some cystine crystals; plurinucle- these symptoms are often related to erosion of corneal epi- ated glomerular podocytes are also characteristic. thelium, leading eventually to keratopathy. Photophobia The general reabsorptive defect of the proximal tubule may be prevented and even completely cured by cysteamine explains the severe hydroelectrolyte imbalance which may eyedrops [9]. Sight may be progressively reduced, leading to 534 Chapter 42 · Cystinosis

blindness in a few patients who already had major ocular Central Nervous System symptoms at an early age and a severe retinopathy. Cataract Cystinosis does not affect general intellectual perform- has been reported [10]. ances. Nevertheless, several kinds of neurologic complica- tions have been reported in cystinosis. Convulsions may Endocrine Disturbances occur at any age, but it is difficult to evaluate the direct re- Hypothyroidism. Thyroid dysfunction usually appears be- sponsibility of cystinosis in this complication aside uremia, tween 8 and 12 years of age, but it may be earlier or later. It is electrolyte desequilibrium, drug toxicity etc. A subtle and rarely overt with clinical symptoms, but rather discovered by specific visuoperceptual defect and lower cognitive per- systematic assessment of thyroid function [4], and it may be formances with sometimes subtle impairment of visual partly responsible for the growth impairment. Cysteamine memory and tactile recognition have been reported [23, was reported to delay or prevent thyroid dysfunction [11]. 24]. More severe CNS abnormalities with various defects have also been described [7, 25]. The clinical symptoms Gonadal Function. Abnormalities in the pituitary testicular include hypotonia, swallowing and speech difficulties, axis with a low plasma testosterone and high FSH/LH level development of bilateral pyramidal signs and walking dif- [12, 13] seem common in male patients with cystinosis. ficulties, cerebellar symptoms and a progressive intellec- They may preclude full pubertal development. Female pa- tual deterioration leading to a pseudo-bulbar syndrome. In tients exhibit pubertal delay but seem to have more normal other cases, acute ischemic episodes may occur with hemi- gonadal functions and there are several reports of successful plegia or aphasia. This cystinotic encephalopathy was only pregnancies. observed above 19 years of age, and at present it is difficult to know its actual incidence. The effectiveness of cysteam- Endocrine Pancreas. Postoperative hyperglycemia and per- ine treatment for the prevention of CNS involvement is not manent insulin-dependent diabetes have been reported in known either. Cysteamine treatment was associated in several series of cystinotic patients after kidney transplanta- some cases with an improvement of neurologic symptoms tion. In patients not treated by cysteamine, 50% had diabe- [25]. Brain imaging in cystinosis may show several types of tes according to the WHO definition [14]. The exocrine abnormalities. Brain atrophy, calcifications and abnormal pancreas is usually not affected except in one reported case features of white matter on magnetic resonance imaging X with steatorrea [15]. (MRI) examination are commonly observed after 15 to 20 years of age [25, 26]. Liver and Spleen Involvement Hepatomegaly and splenomegaly occur in one-third to one-half of the cases after 15 years of age who did not re- 42.1.2 Metabolic Derangement ceive cysteamine [4]. Hepatomegaly is related to enlarged Kupffer’s cells that transform into large foam cells contain- Movement of cystine out of cystinotic lysosomes is signifi- ing cystine crystals. This enlargement may be the cause cantly decreased in comparison with that of normal lyso- of portal hypertension with gastroesophageal varices. somes [27, 28]. Consequently, cystine accumulates in many Splenomegaly is also related to the development of foam tissues including kidney, bone marrow, conjunctiva, thy- cells in the red pulp. Hematological symptoms of hyper- roid, muscle, choroid plexus, brain parenchyma and lymph splenism may be noted. A recent study has shown that cy- nodes. This abnormality is related to a molecular defect of steamine prevents this type of complications [16]. cystinosin, the protein that transports cystine across the lysosomal membrane. The function of this carrier molecule Muscle was demonstrated in a cell model after deletion of the lyso- A distinctive myopathy, potentially leading to a severe somal targeting signal directing cystinosin to the plasma handicap, has been reported in some patients with general- membrane [29, 30]. Cystine transport out of the lysosomes ised muscle atrophy and weakness, mainly of distal muscles is H+ driven. Why lysosomal cystine accumulation leads to of all limbs but with more severe involvement of the interos- cellular dysfunction is not clear. It has been shown that cys- seous muscles and those of the thenar eminence [17, 18]. tine loading of proximal tubular cells in vitro was associated Pharyngeal and oral dysfunction, which may also cause with ATP depletion [31] and inhibition of Na+ dependent voice changes, is often observed and has been attributed to transporters [32]. Cellular cystine excess may also inhibit muscle dysfunction [19, 20]. Pulmonary dysfunction with pyruvate kinase [33], deplete the glutathione cell pool, an extraparenchymal pattern of restrictive lung disease was thereby favouring oxidative stress [34] and apoptosis. This recently reported in a series of adult nephropathic cystinot- knowledge has led to the use of cysteamine which increases ics up to 40 years of age; it was directly correlated with the the transport of cystine out of the lysosome. A knock-out severity of myopathy [21]. It is not clear if a case of cardio- mouse model lacking cystinosin recently reported will cer- myopathy reported in a patient was directly related to car- tainly be helpfull for the understanding of the metabolic diac cystine accumulation [22]. derangement [35]. 535 42 42.1 · Infantile Cystinosis

42.1.3 Genetics Water. The water intake must be adjusted to diuresis, short- term weight variation and, if necessary, plasma protein Nephropathic cystinosis is an autosomal recessive disorder. concentration. Fluid requirement increases with external The gene, mapped to chromosome 17 and named CTNS, temperature and with fever. It is also increased by the encodes a protein of 367 amino acids which has the struc- required mineral supplements. ture of an integral membrane protein with 7 membrane spanning domains and two lysosomal targeting signals [36]. Acid Base Equilibrium. Sodium and potassium bicarbonate, More than 50 mutations in the first 10 exons and in the which have a better gastric tolerance than citrate, must be promotor of the gene have been identified in association given in order to obtain a plasma bicarbonate level between with cystinosis. The most common is a 57 kb deletion found 21 and 24 mmol/l. This is sometimes difficult and may in 76% of patients of European descent. In the other cases, require large amounts of buffer, up to 10–15 mmol/kg. point mutations or shorter deletions are found on both alleles, some of them clustering in certain ethnic and/or Sodium. Sodium losses sometimes remain uncompensated geographical areas [37]. after achieving acid base equilibrium. This is recognizable Adolescent and adult forms have the same mode of by a persistent hyponatremia with failure to thrive. inheritance with mutations that do not disrupt the open reading frame and are generally found in the intertrans- Potassium. Hypokalemia requires potassium supplements membrane loops or in the N-terminal region. in order to maintain serum potassium above 3 mmol/l. Four to 10 mmol/kg are usually necessary to achieve this goal. Prescription of Amiloride at a dose of 2-5 mg/day may help 42.1.4 Diagnostic Tests in some cases.

The reported incidence of the disease is about 1:180,000 live Phosphorus. Hypophosphatemia must be corrected with a births [38]. Cystinosis is ascertained by measurement of the supplement of sodium/potassium phosphate at a dose of free cystine content, usually in leukocytes, which in patients 0.3–1 g/day. The aim is to obtain a plasma phosphate just with nephropathic cystinosis is about 10-50 times normal above 1.0 to 1.2 mmol/l. This poorly tolerated supplement [39]. The assay uses a protein-binding technique on white may be gradually withdrawn after some months or years. blood cells, is very sensitive, and can be carried out on small, Excessive phosphorus prescription may lead to nephrocal- 3 ml blood samples. In cystinosis, the level is usually 5 to cinosis. 15 nmol of 1/2 cystine/mg protein. The technique enables detection of heterozygous carriers with levels of 0.5 to 1.4 Vitamin D Supplementation. Since tubular 1D-hydroxyla- nmol 1/2 cystine/mg protein. In control subjects, cystine tion is diminished in this disease, it is justified to give 1D- or is undetectable or <0.4. Ion exchange column chromatogra- 1D-25-OHD3 (0.10–0.50 µg/day), especially in cases of phy may also be used but is less sensitive. The results symptomatic rickets. These prescriptions must be carefully obtained on polymorphonuclear leukocytes are approxi- adjusted by regular follow-up of serum calcium. mately twice those obtained on mixed leukocytes and this must be taken in consideration when comparing data. The Carnitine supplementation at a dose of 100 mg/kg per day measurements may also be carried out on fibroblasts, con- in four divided doses has been proposed in order to correct junctiva and muscle. S-labeled cystine incorporation in muscle carnitine depletion [41]. cultured skin fibroblasts, amniotic cells, or chorionic villi enables a prenatal diagnosis in the first trimester to be made All these supplements need to be given regularly in order [40]. The diagnosis can also be made by mutation analysis to replace the losses which are permanent. A good way to if a deletion is found in locus D17 S829, or another mutation achieve this goal is to prepare in advance all the supple- in the gene. The use of markers close to this locus when a ments, except vitamin D, in a bottle containing the usual first child is affected also allows prenatal diagnosis. At birth, amount of water for the day. Losses of water, potassium and diagnosis is possible on placenta or cord blood white cells. sodium may be drastically reduced by the prescription of indomethacin at a dose of 1.5–3 mg/kg in two separate doses [42]. It has been shown that the angiotensin convert- 42.1.5 Treatment ing enzyme (ACE) inhibitor, enalapril, diminishes albu- minuria and possibly slows down the degradation of renal The therapy of nephropathic cystinosis is both supportive function [43]. When renal degradation progresses, and the and specific. glomerular filtration rate decreases, indomethacin must be stopped; at this time tubular losses also decrease and the Supportive Treatment of the Tubular Losses mineral supplements must be adjusted and progressively Several abnormalities have to be corrected: tapered off in order to avoid overload, especially with so- 536 Chapter 42 · Cystinosis

dium and potassium. At the dialysis stage, mineral supple- of protein. The drug should be started as soon as the diag- ments are usually no longer necessary. nosis is confirmed [49, 50]. The good results obtained in Feeding problems may require tube or gastric button the treatment of nephropathy have encouraged the use of feeding and in some cases continuous or intermittent total cysteamine in patients who are at risk of developing extra- parenteral nutrition [44]. renal complications. Side effects of the drug, which are related to increased acid output, include nausea and vomit- Renal Replacement Therapy ing and can be managed with omeprazole [51]. Less com- There is no specific requirement for cystinotic children for monly, allergic rashes, seizures and neutropenia are seen. this procedure at this stage. Hemodialysis or continuous In addition, cysteamine is responsible for an unpleasant ambulatory/cyclic peritoneal dialysis (CAPD/CPD) are breath odour so that compliance with 4 doses per day is both effective and applied according to the circumstances. difficult to maintain in the long term, especially in adoles- As for any child with ESRF, kidney transplantation is con- cents [52]. sidered the best approach. Results of kidney transplanta- tion in the European Dialysis and Transplant Association (EDTA) pediatric registry were better than for any other 42.2 Adolescent Cystinosis primary renal disease in children [45]. This is a very rare, milder form of the disease, with later Supportive Treatment of Extrarenal clinical onset and delayed evolution to ESRF. It represents Complications less than 2 or 3% of the cases in a recent epidemiological Hypothyroidism, even if asymptomatic, should be treated study [38]. The first symptoms usually appear after 6–8 with L-thyroxine supplementation. Growth failure, one of years of age. Proteinuria may be misleading because its the most striking complications of nephropathic cystino- severity is sometimes in the nephrotic range. Fanconi syn- sis, was reported to be improved by administration of re- drome may be absent [53] or mild, and tubular losses are combinant growth hormone at a dose of 1 U/kg/week [46]. less important than in infantile cystinosis. The same is true Portal hypertension may lead to ascites and bleeding es- for extrarenal symptoms. ESRF develops around 15 years ophageal varices, rendering a portal bypass necessary. of age in most patients. X Hypersplenism with permanent leukopenia and/or throm- The diagnosis is ascertained by the assessment of the bocytopenia may be an indication for splenectomy. Photo- cystine content of leukocytes, which has been found similar phobia and watering may be improved by local sympto- to that of infantile cases. matic therapy such as vitamin A eye drops, artificial tears, topical lubricants, and thin bandage soft contact lenses. It has been shown that eye drops containing 0.5% cysteamine 42.3 Adult Benign Cystinosis are able to prevent corneal deposits [9], and may decrease and even suppress the deposits already present. Corneal Adult or benign cystinosis was first reported by Cogan et graft has been rarely performed, with variable results. al in 1957 [54]. This exceptional disorder [55] is character- ized by the presence of cystine crystals in the eye and the Specific Therapy bone marrow. Crystals in the cornea are usually found by Several attempts have been made to suppress lysosomal chance examination. The level of cystine in leukocytes is cystine storage. Dietary restriction of sulfur amino acids intermediate between that of heterozygotes and homo- has no effect. Only one drug, cysteamine (HS-CH2-NH2), zygotes for nephropathic cystinosis. All systemic manifes- has been employed in cystinosis with apparent benefit, as tations of the other forms of cystinosis are lacking. The shown in a prospective study [47]. Cysteamine is now com- mutations in the CTNS gene that have been found in these mercially available as cysteamine bitartrate (Cystagon). patients encode a protein that allows sufficient residual The dose is progressively increased from 10 to 50 mg/kg of cystine transport. cysteamine base per day. Cysteamine is rapidly absorbed and its maximum effect, assessed by cystine assay in leuko- References cytes, occurs after 1-2 h, and lasts no longer than 6 h [48].

Consequently, it has to be given in 4 separate doses – one 1. Broyer M, Guillot M, Gubler MC, Habib R (1981) Infantile cystinosis: every 6 h – in order to obtain the best prevention of cystine a reappraisal of early and late symptoms. Adv Nephrol 10:137- accumulation. Careful monitoring of polymorphonuclear 166 leukocyte cystine content is essential since the response to 2. Theodoropoulos DS, Shawker TH, Heinrichs C, Gahl WA (1995). cysteamine is variable. Polymorphonuclear leukocyte cys- Medullary nephrocalcinosis in nephropathic cystinosis. Pediatr Nephrol 9:412-418 tine content should be determined 6 hours after the last 3. Van’t Hoff WG, Ledermann SE, Waldron M, Trompeter RS (1995). dose and just prior the next: the aim is to keep cystine con- Early-onset chronic renal failure as a presentation of infantile neph- tent under 2, or better, under 1 nmol of 1/2 cystine per mg ropathic cystinosis. Pediatr Nephrol 9:483-484 537 42 References

4. Broyer M, Tete MJ, Gubler MC (1987) Late symptoms in infantile 28. Gahl WA, Tietze F, Bashan N (1983) Characteristics of cystine coun- cystinosis. Pediatr Nephrol 1:519-524 tertransport in normal and cystinotic Lysosome-rich granular frac- 5. Gahl WA, Kaiser-Kupfer MI (1987) Complications of nephropathic tions. Biochem J 216:393-400 cystinosis after renal failure. Pediat Nephrol 1:260-268 29. Kalatzis V, Cherqui S, Antignac C, Gasnier B (2001) Cystinosin, the 6. Geelen JM, Monnens LA, Levtchenko EN (2002) Follow-up and protein defective in cystinosis, is a H(+)-driven lysosomal cystine treatment of adults with cystinosis in the Netherlands. Nephrol transporter. EMBO J 20:5940-5949 Dial Transplant 17:1766-1770 30. Kalatzis V, Nevo N, Cherqui S et al (2004) Molecular pathogenesis of 7. Theodoropoulos DS, Krasnewich D, Kaiser-Kupfer MI, Gahl WA cystinosis: effect of CTNS mutations on the transport activity and (1993). Classic nephropathic cystinosis as an adult disease. JAMA subcellular localization of cystinosin. Hum Mol Genet 13:1361- 270:2200-2204 1371 8. Dureau P, Broyer M, Dufier JL (2003) Evolution of ocular manifesta- 31. Foreman JW, Bowring MA, Lee J et al (1987) Effect of cystine dime- tions in nephropathic cystinosis: a long-term study of a population thyl ester on renal solute handling and isolated renal tubule trans- treated with cysteamine. J Pediatr Ophthalmol Strabismus 40:142- port in the rat: a new model of the Fanconi syndrome. Metabolism 146 36:1185-1191 9. Gahl WA, Kuehl EM, Iwata F et al (2000) Corneal crystals in nephro- 32. Cetinkaya I, Schlatter E, Hirsch Jr et al (2002) Inhibition of Na(+)- pathic cystinosis: natural history and treatment with cysteamine dependent transporters in cystine-loaded human renal cells: elec- eyedrops. Mol Genet Metab 71:100-120 trophysiological studies on the Fanconi syndrome of cystinosis. J 10. Fahey DK, Fenton S, Mohamed Q, Logan P (2001) Cystinosis, cata- Am Soc Nephrol 13:2085-2093 ract surgery, and corneal erosions. J Cataract Refract Surg 27:2041- 33. Feksa LR, Cornelio A, Dutra-Filho CS et al (2004) Inhibition of pyru- 2043 vate kinase activity by cystine in brain cortex of rats. Brain Res 11. Kimonis VE, Troendle J, Rose SR et al (1995) Effects of early cysteam- 1012:93-100 ine therapy on thyroid function and growth in nephropathic cysti- 34. Chol M, Nevo N, Cherqui S et al (2004) Glutathione precursors nosis. J Clin Endocrinol Metab 80:3257-3261 replenish decreased glutathione pool in cystinotic cell lines. Bio- 12. Chik C L, Friedman A, Merriam G R, Gahl WA (1993) Pituitary-tes- chem Biophys Res Commun 324:231-235 ticular function in nephropathic cystinosis. Ann Intern Med 35. Cherqui S, Sevin C, Hamard G et al (2002) Intralysosomal cystine 119:568-575 accumulation in mice lacking cystinosin, the protein defective in 13. Tete MJ,Broyer M (1999) Thyroid and gonads involvement in cysti- cystinosis. Mol Cell Biol 22:7622-7632 nosis. In: Broyer M (ed) Cystinosis. Elsevier, Paris, pp 70-74 36. Town M, Jean G, Cherqui S et al (1998) A novel gene encoding an 14. Robert JJ, Tête MJ, Guest G et al (1999) Diabetes mellitus in patients integral membrane protein is mutated in nephropathic cystinosis. with infantile cystinosis after renal transplantation. Pediatr Nephrol Nat Genet 18:319-324 13:524-529 37. Kalatzis V, Antignac C (2003) New aspects of the pathogenesis of 15. Fivusch B, Flick J, Gahl WA (1988) Pancreatic exocrine insufficiency cystinosis. Pediatr Nephrol 18:207-215 in a patient with nephropathic cystinosis. J Pediatr 112:49-51 38. Cochat P, Cordier, Lacôte C, Saïd MH (1999) Cystinosis: epidemiol- 16. Gagnadoux MF, Tête MJ, Guest G et al (1999) Hepatosplenic disor- ogy in France. In: Broyer M (ed) Cystinosis. Elsevier, Paris, pp 28-35 ders in nephropathic cystinosis. In: Broyer M (ed) Cystinosis. Else- 39. Schneider JA, Wong V, Bradley K, Seegmiler JE (1968) Biochemical vier, Paris, pp 70-74 comparisons of the adult and childhood forms of cystinosis. N Engl 17. Gahl WA, Dalakas M, Charnas L, Chen K (1988). Myopathy and J Med 279:1253-1257 cystine storage in muscles in a patient with nephropathic cystino- 40. Patrick AD, Young EP, Mossman J et al (1987) First trimester diag- sis. N Engl J Med 319:1461-1464 nosis of cystinosis using intact chorionic villi. Prenat Diagn 7:71- 18. Vester U, Schubert M, Offner G, Brodehl J (2000) Distal myopathy in 74 nephropathic cystinosis. Pediatr Nephrol 14:36-38 41. Gahl WA, Bernardini IM, Dalakas MC et al (1993) Muscle carnitine 19. Sonies BC, Ekman EF, Andersson HC et al (1990) Swallowing dys- repletion by long-term carnitine supplementation in nephropathic function in nephropathic cystinosis. N Engl J Med 323:565-570 cystinosis. Pediatr Res 34:115-119 20. Trauner DA, Fahmy RF, Mishler DA (2001) Oral motor dysfunction 42. Haycock GB, Al-dahhan J, Mak RHK, Chantler C (1982) Effect of in- and feeding difficulties in nephropathic cystinosis. Pediatr Neurol domethacin on clinical progress and renal function in cystinosis. 24(5):365-368 Arch Dis Child 57:934-939 21. Anikster Y, Lacbawan F, Brantly M et al (2001) Pulmonary dys- 43. Levtchenko E, Blom H, Wilmer M et al (2003) ACE inhibitor enalapril function in adults with nephropathic cystinosis. Chest 119:394- diminishes albuminuria in patients with cystinosis. Clin Nephrol 401 60:386-389 22. Dixit MP, Greifer I (2002) Nephropathic cystinosis associated with 44. Elenberg E, Norling LL, Kleinman RE, Ingelfinger JR (1998) Feeding cardiomyopathy: a 27-year clinical follow-up. BMC Nephrol 3:8 problems in cystinosis. Pediatr Nephrol 12:365-370 23. Colah S, Trauner DA (1997) Tactile recognition in infantile nephro- 45. Broyer M on behalf of the EDTA registry committee (1989) Kidney pathic cystinosis. Dev Med Child Neurol 39:409-413 transplantation in children, data from the EDTA registry. Transplant 24. Ballantyne AO, Trauner DA (2000) Neurobehavioral consequences Proc 21:1985-1988 of a genetic metabolic disorder: visual processing deficits in infan- 46. Wühl E, Haffner D, Offner G et al (2001) Long-term treatment with tile nephropathic cystinosis. Neuropsychiatry Neuropsychol Behav growth hormone in short children with nephropathic cystinosis. J Neurol 13:254-263 Pediatr 138:880-887 25. Broyer M, Tete MJ, Guest G et al (1996) Clinical polymorphism of 47. Gahl WA, Reed G, Thoene JG et al (1987) Cysteamine therapy for cystinosis encephalopathy. Results of treatment with cysteamine. children with nephropathic cystinosis. N Engl J Med 316:971-977 J Inherit Metab Dis 19:65-75 48. Belldina EB, Huang MY, Schneider JA et al (2003) Steady-state phar- 26. Nichols S, Press G, Schneider J, Trauner D (1990). Cortical atrophy macokinetics and pharmacodynamics of cysteamine bitartrate in and cognitive performance in infantile nephropathic cystinosis. paediatric nephropathic cystinosis patients. Br J Clin Pharmacol. Pediatr Neurol 6:379-381 56:520-525 27. Gahl WA, Bashan N, Tietze F (1982) Cystine transport is defective 49. Da Silva VA, Zurbrug RP, Lavanchu P et al (1985) Long term treat- in isolated leukocyle Lysosomes from patients with cystinosis. ment of infantile nephropathic cystinosis with cysteamine. N Engl Science 217:1263-1265 J Med 313:1460-1463 538 Chapter 42 · Cystinosis

50. Kleta R, Bernardini I, Ueda M et al (2004) Long-term follow-up of well-treated nephropathic cystinosis patients. J Pediatr 145:555- 560 51. Dohil R, Newbury RO, Sellers ZM et al (2003) The evaluation and treatment of gastrointestinal disease in children with cystinosis receiving cysteamine. J Pediatr 143:224-230 52. Schneider JA (2004) Treatment of cystinosis: Simple in principle, difficult in practice. Pediatrics 145:436-438 53. Hory B, Billerey C, Royer J, Saint Hillier Y (1994) Glomerular lesions in juvenile cystinosis: report of 2 cases. Clin Nephrol 42:327-330 54. Cogan DG, Kuwabara T, Kinoshita J et al (1957) Cystinosis in a adult. JAMA 164:394 55. Anikster Y, Lucero C, Guo J et al (2000) Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations. Pediatr Res 47:17-23

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