Cystinosis: a review
© Elmonem et al. 2016
Received: 28 October 2015
Accepted: 15 April 2016
Published: 22 April 2016
Cystinosis is the most common hereditary cause of renal Fanconi syndrome in children. It is an autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene encoding for the carrier protein cystinosin, transporting cystine out of the lysosomal compartment. Defective cystinosin function leads to intra-lysosomal cystine accumulation in all body cells and organs. The kidneys are initially affected during the first year of life through proximal tubular damage followed by progressive glomerular damage and end stage renal failure during mid-childhood if not treated. Other affected organs include eyes, thyroid, pancreas, gonads, muscles and CNS. Leucocyte cystine assay is the cornerstone for both diagnosis and therapeutic monitoring of the disease. Several lines of treatment are available for cystinosis including the cystine depleting agent cysteamine, renal replacement therapy, hormonal therapy and others; however, no curative treatment is yet available. In the current review we will discuss the most important clinical features of the disease, advantages and disadvantages of the current diagnostic and therapeutic options and the main topics of future research in cystinosis.
Cystinosis was first described in literature in 1903 by the Swiss biochemist Emil Abderhalden (1877–1950) as the familial cystine accumulation disease . Abderhalden referred to a child initially encountered by Eduard Kaufmann, Basel, Switzerland (1860–1931). This patient died at the age of 21 months with massive cystine accumulation in multiple organs that were discovered at the postmortem examination. The Dutch pathologist George Lignac (1891–1954) was the first to provide a clear systematic description of the disease in 1924, and the first to associate cystinosis with its major clinical manifestations such as rickets, renal disease and growth retardation . This is why cystinosis was initially termed as the Abderhalden-Kaufmann-Lignac syndrome. Guido Fanconi (1892–1979), the Swiss pediatrician, also substantially contributed to the understanding of cystinosis by explaining the urinary substance losing nature of the disease . Hence, cystinosis was also recognized in the literature as the Lignac-Fanconi syndrome.
The currently used term “cystinosis” is a modification from the German term “Cystindiathese” or “hereditary cystine disease” which was initially used by Emil Abderhalden to describe the disease in 1903 and was modified in the English literature to “cystine disease” then “cystinosis”. Cystinosis (ORPHA213) is a rare autosomal recessive lysosomal storage disorder in which the amino acid cystine accumulates in the lysosomes of cells . Cystinosis is one of the few rare diseases having a specific treatment. The aminothiol cysteamine, used for the treatment of cystinosis for over 20 years now , can deplete the intralysosomal cystine through the reduction of cystine, and the formation of cysteine and a cysteamine-cysteine mixed disulfide which exits the lysosome via the cationic amino acid transporter PQLC2, thus bypassing the original genetic and biochemical defects of the disease [6, 7].
Cystinosis is a systemic disease and cystine crystals, the pathologic landmark, accumulate in all body cells and tissues. Although cystinosis is a monogenic disease, it has three major clinical presentations depending on the severity of mutations affecting the CTNS gene: the infantile nephropathic form (MIM: 219800, ORPHA411629), the juvenile nephropathic form (MIM: 219900, ORPHA411634) and the ocular non-nephropathic form (MIM: 219750, ORPHA411641) .
In the current review, we describe the clinical spectrum of the disease, the diagnostic and management protocols and the anticipated advances in the near future.
Nationwide birth prevalence data concerning cystinosis are only reported in few populations. The overall incidence rates reported in France , Australia , Germany , Denmark  and Sweden  were 1:167,000, 1: 192,000, 1: 179,000, 1:115,000 and 1:260,000 live births, respectively. Higher incidence rate is observed in selected populations with detected founder mutations as in the province of Brittany, France (1:26,000 live births)  or in the Saguenay-Lac-St-Jean, Quebec, Canada (1:62,500 live births) . The highest birth frequency rate ever reported was in the Pakistani ethnic group living in the West Midlands, UK (1: 3,600) . Since cystinosis is an autosomal recessive disease, its incidence is expected to be affected by the extent of consanguinity in the community. Accurate statistical data about the incidence of cystinosis in regions with high consanguinity such as Middle East and North Africa are still lacking; however, cystinosis was fairly commonly detected among a large cohort of different lysosomal storage disorders diagnosed over a six year period in Egypt (29/211 patients (13.7 %)) .
Cystinosis is caused by bi-allelic mutations in the CTNS gene (17p13.2) encoding cystinosin, which is a lysosomal cystine-proton co-transporter. Consequently, cystine accumulates in the lysosomes of affected cells and forms crystals in low lysosomal pH .
Clinical description and complications
Three clinical forms of cystinosis can be distinguished, depending on the age of presentation and the degree of renal disease severity.
The infantile nephropathic form is the most frequent (95 %) and the most severe type of cystinosis. The renal phenotype consists of renal Fanconi syndrome, and a consecutively progressive loss of glomerular function leading to end-stage renal failure [4, 21, 22]. Asymptomatic aminoaciduria is the first manifestation of renal Fanconi syndrome in humans [23, 24] with urinary losses of amino acids being 6 to 16 times increased compared to the normal amount . The earlier loss of expression of apical proximal tubular receptors megalin/cubilin and SGLT-2, and NaPi-IIa transporters preceding cell atrophy in a mouse model of cystinosis, provides an explanation for the early proteinuria, glucosuria, and phosphaturia [26, 27].
By the age of 6 to 12 months, selective proximal tubular dysfunction develops into the full-blown renal Fanconi syndrome, characterized by excessive urinary loss of amino acids, sodium, potassium, bicarbonate, magnesium, carnitine, calcium, phosphate, glucose and low molecular (LMW) to intermediate molecular weight (IMW) proteins [23, 25]. Infants present with failure to thrive, polyuria, polydipsia, episodes of severe dehydration and electrolyte imbalance, vomiting, constipation and sometimes vitamin D resistant rickets. Laboratory findings may include hypokalemia, metabolic acidosis, hypophosphatemia, hypocalcemia, low carnitine levels and less frequently hyponatremia. However, metabolic alkalosis in case of a Bartter-like presentation has also been reported [28, 29].
A small group of cystinosis patients (5 %) is diagnosed during late childhood or adolescence with the juvenile (late onset) form of cystinosis . Patients present with a variable spectrum of features, ranging from isolated asymptomatic proteinuria, a mild renal Fanconi syndrome, to an overt nephrotic syndrome and usually they do not develop remarkable growth retardation. Generally, there is a slower progression rate to ESRD and extra-renal complications. In small series, four out of 14 patients with juvenile cystinosis developed ESRD at 12, 21, 27 and 28 years of age .
The adult, non-nephropathic ocular form of cystinosis is characterized only by photophobia due to corneal cystine accumulation, and rarely presents before adulthood . The kidneys and other organs are spared from symptoms. In one family the co-existence of ocular and late-onset forms of cystinosis has been reported, implying the need of regular renal function controls in patients with ocular cystinosis .
Being a systemic lysosomal storage disorder cystinosis manifests in almost all tissues and organs, and, although most systemic features are manifested relatively late during the course of the disease, the pathological processes behind these manifestations, especially cystine accumulation, usually start early. Nearly all nephropathic cystinosis patients who did not receive early cystine-depleting therapy or those who are not compliant, will develop major extra-renal symptoms including retinal, endocrinological and neuromuscular complications by the age of 30 years .
Progressive cystine accumulation and crystal formation in thyroid follicular cells causes fibrosis and atrophy leading to primary hypothyroidism [45, 46], manifesting in the majority of cystinosis patients (50–70 %) from the second decade of life . Earlier thyroid changes affecting thyroglobulin synthesis and iodo-thyroglobulin processing might be responsible for subclinical hypothyroidism with TSH elevation and normal T3 and T4 plasma concentrations, as it has been shown in a mouse model of cystinosis .
Endocrine and exocrine pancreatic insufficiency have been also reported in cystinotic patients, usually after renal allograft transplantation [48, 49]. Fifty percent of infantile cystinosis patients by the age of 18 develop slow progressive loss of insulin secretion and C-peptide production leading to glucose intolerance and diabetes mellitus . Hepatomegaly and/or splenomegaly are present in about one third of patients by the age of 15 years, however, liver function usually remains unaffected .
In male cystinosis patients, primary hypogonadism is a frequent finding (70 %) [51–53]. Recently, Besouw et al. have shown that although azoospermia was present in all studied male cystinosis patients under cysteamine therapy, spermatogenesis was documented on a testicular biopsy specimen in one renal transplant patient . In females, although delayed puberty is sometimes observed, normal pubertal development is also possible and in contrast to males, cystinotic females are usually fertile .
Central nervous system involvement is evident in a subgroup of cystinotic patients and becomes more frequent with advancing age. Neurological findings include hypotonia, tremor, speech delay, gross and fine motor impairment, idiopathic intracranial hypertension, neurocognitive dysfunction, behavioral problems and encephalopathy [56–61]. Despite normal IQ scores, cystinosis patients have significantly poorer performance in visual spatial and visual memory skills than normal individuals and, interestingly, their highest scores are in the area of auditory short-term memory, which could be a compensatory mechanism for their poor visual memory [58, 62]. A recent study in cystinosis patients aged 3–7 years, using the MRI based technique, diffusion tensor imaging (DTI) detected the early selective white matter microstructural changes in the form of bilaterally decreased fractional anisotrophy and increased mean diffusivity in the inferior and superior parietal lobules in children with cystinosis corresponding to the areas of the dorsal and ventral visual pathways , thus giving the pathological explanation for the early onset of poor visual spatial and visual memory skills. Other common pathological findings usually observed at older age include cerebral cortical atrophy, non-absorptive hydrocephalus, demyelination, and vacuolar, necrotic and spongiform changes [57, 58].
A distal vacuolar myopathy presenting as progressive distal muscle wasting and weakness, has been observed in about 24 % of renal transplant cystinosis patients [64, 65]. Myopathy generally affects patients from their second decade of life. Myopathy changes on EMG can be present in asymptomatic patients, suggesting that clinically overt muscle weakness might be a late sign of cystinotic myopathy . In post-transplant cystinotic patients who did not receive long-term cystine-depleting therapy, cystinotic myopathy may cause an extraparenchymal pattern of restrictive lung disease . Swallowing dysfunction occurs in more than half of patients with myopathy and its severity also positively correlates with the number of years without cysteamine therapy . As a result, aspiration pneumonia constitutes a severe and potentially lethal complication.
Other observed features related to skin, hair and salivary glands have also been reported such as congenital hypopigmentation, premature skin ageing, impaired sweating and salivation and progressive coarse facial features due to subcutaneous cystine infiltration . According to our experience, not only European patients, but also some patients from other ethnic backgrounds can present with characteristic blond hair and white skin. Recently, cystinosin was implicated in the regulation of melanin synthesis as CTNS silencing in a melanoma cell model led to over 50 % reduction in pigment production .
Differential diagnosis of cystinosis according to the most common presenting manifestations
Other characteristic features at presentation
Proximal renal tubular acidosis
Tyrosinemia type I
Hepatomegaly, mental retardation
Lethargy, jaundice, bleeding disorders, cataract, intellectual disability
Hereditary fructose intolerance
Seizures, irritability, poor feeding, lethargy, liver disease
Copper transporting P-type ATPase
Liver disease, neuropsychiatric manifestations, Kayser-Fleischer ring in the cornea
Phosphatidylinositol 4,5-diphosphate 5-phosphatase
Congenital cataract, glaucoma, intellectual disability, hypotonia, seizures, behavioral problems
Chloride Channel Protein number 5
Low molecular weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, progressive renal failure
- Leigh syndrome
Cytochrome C oxidase assembly protein
Encephalopathy, myopathy, respiratory istress, deterioration of cognitive function
- Gracile syndrome
S. cerevisiae bcs1 protein homolog
Severe lactic acidosis, hypoglycemia, cholestasis, iron overload
- HUPRA syndrome
Hyperuricemia, pulmonary hypertension, renal failure, alkalosis
- Mitochondrial DNA depletion syndrome 8
Ribonucleotide reductase small subunit 2 like
Neonatal hypotonia, lactic acidosis, neurologic deterioration
- Mitochondrial DNA depletion syndrome 13
Leucine rich repeat protein 4
Hypotonia, lactic acidois, microcephaly, congenital cataract
Heavy metal toxicity: Lead, cadmium
Anemia, abdominal pain, encephalopathy, osteomalacia, neurological manifestations
Hypophosphatemic nephrolithiasis/osteoporosis I
Sodium-phosphate cotransporter, member 1
Nephrolithiasis, osteoporosis, multiple fractures
Hypophosphatemic nephrolithiasis/osteoporosis II
Sodium/hydrogen exchanger regulatory factor 1
Nephrolithiasis, osteoporosis, hypocalcemia, hypoparathyroidism
Autosomal dominant hypophosphatemic rickets
Fibroblast growth factor 23
Fatigue, bony pains, bone deformities
Autosomal recessive hypophosphatemic rickets
Dentin matrix acidic phosphoprotein 1
Retarded skeletal growth, abnormal mineralization
Hereditary hypophosphatemic rickets with hypercalciuria
Sodium-phosphate cotransporter, member 3
Elevated serum 1,25-dihydroxy vitamin D levels, hypercalciuria, osteomalacia, nephrolithiasis, nephrocalcinosis
Vitamin D dependent rickets type I
Hypotonia, muscle weakness, seizures
Vitamin D dependent rickets type II
vitamin D receptor
Alopecia, hypocalcemia, secondary hyperparathyroidism, osteomalacia, osteitis fibrosa cystica
Cystic fibrosis transmembrane conductance regulator protein
Frequent chest infections, pancreatic insufficiency
Fatigue, anemia, poor cognitive function, behavioral changes, history of poor socioeconomic standard
Lethargy, fatigue, dry skin, cold intolerance, constipation, mental subnormality
- GH deficiency
Short stature with general good health, normal intelligence
Cystinosis is also responsible for some cases of childhood renal failure, and should be considered in every young patient presenting with renal failure of unknown origin .
Due to the availability of specific cysteamine therapy, early diagnosis and management of cystinosis have a great impact on the clinical outcome of patients. There are three main diagnostic modalities for cystinosis. The current gold standard is the detection of elevated cystine levels in white blood cells (WBCs), being extremely sensitive and precise for the disease. Molecular testing of the relatively small CTNS gene (12 exons but only 10 are coding) is also a well- established technique revealing 95 % of disease causing mutations. The third clinically used confirmatory option is the detection of the characteristic corneal cystine crystals by slit lamp examination .
Oshima et al. established a highly sensitive and specific method for cystine measurement in WBCs in 1974 . Their assay was based on the selective binding between cystine in the WBC sample and cystine binding protein (CBP) isolated from Escherichia coli in the presence of a competitor external [14C] cystine, with the resultant bound radioactivity being inversely proportional to cystine concentration in the unknown sample. Although still used in few laboratories, this method is widely replaced now by high performance liquid chromatography (HPLC) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods [71, 72]. Newly diagnosed cystinotic patients have WBC cystine levels in the range of 3–20 nmol half-cystine/mg protein, while control individuals and heterozygous carriers have levels <0.2 and <1.0 nmol half-cystine/mg protein, respectively. The main source of the assay variability lies in the method applied for WBCs separation, and whether it is a mixed leucocyte or polymorphonuclear leucocyte population, thus, the type of cells and the separation method should be highly standardized for each laboratory. Nevertheless, the instrumentations and techniques involved, so far, in cystine measurement are sophisticated enough to limit its use to few university hospitals and research centers mainly in the developed world. This is further complicated by the sample sensitivity to storage and transportation conditions, therefore so far most developing nations are still lacking the assay .
Being a monogenic disease, molecular diagnosis is efficient as a confirmatory tool; however, it is usually more time consuming than cystine measurement. In about 5 % of patients pathogenic mutations are not easily discovered by the usual CTNS gene sequencing, being either deeply intronic, in the promoter region or not commonly encountered large deletion or duplication .
The visualization of corneal cystine crystals is the main diagnostic method for cystinosis in developing nations. Although reliable and relatively cheap, it needs a considerably experienced ophthalmologist to identify and grade the crystals properly. Cystine crystals also do not appear in the slit lamp examination until the second year of life which delays the start of specific therapy in most patients .
Another possible non-invasive evaluator of the cystine crystal load is the reflectance confocal microscopy (RCM). Chiaverini et al. have shown that RCM is able to detect dermal cystine deposition in young patients with cystinosis . Cystine deposits were visualized as bright, round, or oval-shaped dermal particles of variable size. These particles appear to be specific in cystinosis, as no particles were identified in control subjects. The nature of the deposits was further confirmed by electron microscopy showing that the particles corresponded to crystalline cystine within fibroblasts in the reticular dermis . The test is rapid (5 min), painless and tolerable even in the youngest children.
Because of the availability of cystine-depleting therapy, the development of a newborn screening method is very tempting; however, it is not available so far. The evaluation of cystine levels in blood spots would be logical to consider but many technical difficulties stand in the way including the much higher sensitive instrumentation needed to quantify cystine reliably in a minute amount of sample (the current ideal sample for WBC cystine is 5–10 ml of blood), the difficulty to prevent the spontaneous oxidation of cysteine into cystine in stored blood spots and the interference from serum cystine levels which are completely not related to the disease . A recent study has detected the elevation of sedoheptulose in dried blood spots of patients homozygous for the 57-kb deletion mutation by tandem mass spectrometry . This is the result of the simultaneous deletion of the CTNS upstream gene (CARKL/SHPK) which encodes the enzyme sedoheptulokinase. Nonetheless, cystinotic patients not harboring this mutation, or even heterozygous would have a completely normal blood spot sedoheptulose levels, making the clinical use of this method very limited.
Detection of most CTNS mutations is accomplished by sequencing individual exons and the adjacent splice sites, while large deletions and insertions could be detected by other molecular techniques such as allele specific PCR, multiplex ligation-dependent probe amplification (MLPA) or fluorescence in-situ hybridization (FISH) [79–81].
Antenatal diagnosis of cystinosis through the detection of elevated cystine in cells of fetal origin has been available for many years now . Two main sample types are used for this purpose, either chorionic villous biopsy sample (taken at 8–9 weeks of gestation) or cultured amniotic cells (14–16 weeks of gestation). Cystine can be directly quantified in these cells with either HPLC or LC-MS/MS . DNA analysis for detecting mutant alleles is currently the most frequently used antenatal screening method, but to reach a molecular diagnosis in a timely fashion for an informed decision, knowing the pathogenic mutation(s) in a previous sibling is highly favored.
Optimal symptomatic treatment of the renal Fanconi syndrome and extra-renal complications, combined with cysteamine, the specific cystine-depleting therapy represent the mainstay of cystinosis treatment . Early diagnosis is of vital importance to ensure better control of cystinosis as the early start of specific treatment ensures better growth and delays the onset of ESRD and most of extra renal complications.
The supportive, symptomatic treatment of cystinosis aims to (1) maintain an adequate fluid- and electrolyte substitution and safeguard the acid–base balance, (2) provide nutritional support, (3) prevent the development of rickets and (4) ensure adequate substitution of needed hormones.
Due to their polyuria and impaired sweating ability, cystinosis patients should have access to water and toilets at all times, and should avoid excessive exposure to heat and sun in order to maintain proper hydration . Electrolyte substitution is provided through oral solutions of sodium bicarbonate or sodium/potassium citrate. Substitution with sodium or potassium phosphate and 1–25-(OH)2 cholecalciferol should be initiated from early childhood to compensate for the phosphate imbalance and to prevent rickets in patients with preserved GFR. Sodium, potassium, bicarbonate and phosphate need to be monitored frequently, and the dose of substitution needs to be adjusted accordingly. If phosphate, 1,25-(OH) 2 cholecalciferol and bicarbonate are excessively substituted, nephrocalcinosis may occur [85, 86]. There is no consensus on the systematic use of indomethacin in order to enhance sodium reabsorption at the ascending limb of the loop of Henle and the collecting ducts ; however, this treatment can be useful to decrease polyuria and reduce electrolyte losses.
Carnitine replacement has been suggested because of low plasma and muscle carnitine levels in cystinosis patients, though clinical improvement with this therapy has not been proven yet [87, 88]. The majority of cystinosis patients experience a progressive failure to thrive for which a high-caloric diet is recommended in association with other lines of treatment . Feeding by nasogastric tube should be considered early, especially in children with anorexia, complaints of anorexia and frequent vomiting, or to facilitate administration of medical treatment.
Because of the multiple endocrinopathies caused by cystinosis, hormone replacement therapy plays an important role in symptomatic care. Careful monitoring of the thyroid, and later pancreatic function during childhood and adolescence, is important. In the absence of poor cystine-depleting therapy and renal insufficiency, growth hormone replacement therapy can be considered to prevent growth retardation despite a normal growth hormone axis ; however, the long term implications of growth hormone replacement in patients with cystinosis is unclear. Currently, insufficient data is available on the pathophysiology of the azoospermia observed in male cystinosis patients. Testosterone supplementation is indicated in patients with a primary testicular failure and low plasma testosterone levels .
Angiotensin converting enzyme inhibitors (ACE inhibitors) are a well-established treatment to reduce proteinuria of glomerular origin and to slow down the decline of glomerular filtration rate in chronic renal failure. Greco et al. reported over 20 years of follow up in cystinosis patients, during which the use of ACE inhibitors was associated with slower deterioration of renal function ; however, because of the risk of hypotension and consequent renal function decline, ACE inhibitors must be used with caution in patients with extracellular volume and sodium depletion . The combined use of ACE inhibitors together with indomethacin should be strictly avoided.
In case of renal failure, renal transplantation is the treatment of choice. As renal disease does not recur in the transplanted kidney, kidney graft cures the ESRD, but has no effect on the multi-systemic complications. Therefore, cystine-depleting therapy has to be taken lifelong. Although cystine crystals have been observed in the renal graft, they are of no pathological nor clinical significance since they arise from the host mononuclear cells . In comparison to other renal diseases, renal graft survival in cystinotic patients has been reported as superior, although this has not been demonstrated in ERA-EDTA registries [94–97].
Since fluid and electrolyte losses generally decrease during renal replacement therapy, nephrectomy of the native kidneys is rarely needed. As other post-transplant patients, all cystinosis patients should be monitored for immunodeficiency and infections related to immunosuppressive agents after renal transplantation.
The aminothiol cysteamine (beta-mercaptoethylamine) is currently the only target-specific treatment for cystinosis patients. It aims to deplete lysosomal cystine in all body cells and tissues. The most commonly used cysteamine preparation is the immediate-release cysteamine bitartrate (IR-CYS) (Cystagon®, Mylan Pharma, Morgantown, WV, USA and Orphan Europe, Paris, France). The drug has been approved for clinical use in cystinosis in 1994 in the USA, and in 1997 in Europe .
Cysteamine improves overall prognosis by delaying the progression to end-stage renal disease by 6 to 10 years, and thus the need for renal transplantation during childhood [8, 30, 85, 99–103]. Cysteamine has also been shown to prevent or postpone the development of some extra-renal complications. It reduces the need for thyroid hormone replacement therapy, depletes the muscle parenchyma of cystine hereby reducing myopathy, delays pulmonary and pancreatic dysfunction and prevents growth failure when initiated in early infancy [30, 99–101]. In a large cohort of adult cystinotic patients, the frequency of diabetes and myopathy decreased from 28 % to 0 % and from 60 % to 0 %, respectively when the duration of cysteamine treatment exceeded 20 years, while the percentage of hypothyroidism decreased from 87 % to 56 % in patients having cysteamine for more than 8 years .
The leucocyte cystine level is today the only available biomarker for monitoring the effectiveness of oral cystine-depleting therapy. The tissue cystine levels at which progressive renal failure and extra-renal complications can be prevented, are unknown. Hence, the 90th percentile of cystine levels in polymorphonuclear cells (<1 nmol ½ cystine per mg protein), seen in heterozygotes, is used as the upper cystine limit. The leucocyte cystine content returns to its initial levels about 6 h after the last administration, therefore the immediate release formulation of cysteamine bitartrate (IR-CYS) has to be taken at a 6-h interval. Greater compliance with oral cysteamine therapy yields greater preservation of renal glomerular function as for every year of excellent cystine depletion, nearly one year of renal function was preserved .
Cysteamine is a potent gastric acid-secretagogue and has been used to induce duodenal ulceration in laboratory animals . In children, a fourfold increase in gastric acid production and 50 % increase in serum gastrin levels in comparison to baseline levels, have been reported [107, 108]. Hence, gastrointestinal complaints as nausea, dyspepsia, vomiting and epigastric pain are frequent and cause cysteamine intolerance in approximately 14 % of patients [30, 99, 109]. In our experience, these complaints can be minimized by the low start and gradual increase in cysteamine dosage. Use of proton pump inhibitors has been found effective in the management of gastric acid hypersecretion and ulcerogenicity . In selected patients, a Nissen fundoplication may be of help. A small amount of cysteamine is also metabolized into sulfur-containing compounds (dimethylsulfide, methanethiol), which cause halitosis and a bad sweat odor. For this, oral supplements of riboflavin and chlorophyll tablets are used by some patients [84, 111].
It has been suggested to calculate the cysteamine dose based on body surface area (1.30 g/m2/day; maximum of 1.95 g/m2/day) instead of body weight (50 mg/kg/day), to avoid overdosing . Recently, some patients treated with high cysteamine doses (>1.95 g/m2/day) were reported to have skin striae, bone pain, myalgia, and endothelial proliferative lesions on the elbows showing reactive angioendotheliomatosis on skin biopsy. These adverse events developed in a small proportion of patients, and, while bone and joint pain remained in some patients, cutaneous manifestations resolved after lowering the dose of cysteamine .
Other reported adverse effects of cysteamine include hyperthermia, lethargy, neutropenia, seizures and allergic rash . Fortunately, these effects are reversible, and when cysteamine is started at a low dose and increased gradually, these complaints can be prevented . Based on the observation of dose-related (100–150 mg/kg/day) development of a cleft palate, kyphosis, intrauterine growth retardation and intrauterine death with cysteamine treatment in the rat, it is recommended to discontinue cysteamine in women planning pregnancy [115, 116]. The potential risks of cysteamine discontinuation for several months should be carefully balanced against the desire to have children.
Taken together, current cysteamine therapy with its strict dosing regimen and significant adverse effects, imposes a significant burden on cystinosis patients. It has been estimated that only one third of patients are able to adhere to the strict dosing schedule . Poor compliance leads to a less favorable prognosis with progressive renal function deterioration and poor growth .
Treatment guidelines for cystinosis
Renal Fanconi syndrome
Free water supply
Day and night
Special attention for sufficient hydration in case of fever, diarrhea and external heat
Early tube feeding may be needed for water requirements
high caloric intake
130 % of RDI
Tube feeding can be needed in young infants
Renal salt loosing
sodium citrate or sodium bicarbonate
Oral 2–10 mmol/kg
citrate or bicarbonate as sodium & potassium salts
Oral 5–15 mmol/kg
Normal bicarbonate level (21–24 mmol/l) should be achieveda
potassium citrate or potassium chloride
Oral 2–10 mmol/kg
Potassium level > 3 mmol/l should be achieveda
sodium or potassium phosphate
Oral 30–60 mg elementary P/kg
Normal age-related phosphate levels should be achieveda
High doses of phosphate supplements can cause or aggravate nephrocalcinosis
Treatment of rickets
Oral 10–25 μg
Follow-up serum calcium concentration to prevent hypercalcemia
alpha-calcidol or calcitriol
Oral 0.04–0.08 μg/kg
no data is available in cystinosis
1–10 mg/day depending on age and serum copper levels
Chlorophyllin tablets that are used to mitigate halitosis contain 4 mg of elemental copper per tablet
Difficult to control electrolyte losses and polyuria
Oral 1–3 mg/kg
Follow-up serum creatinine
Discontinue in case of dehydration
Concomitant use with ACE inhibitors is contra-indicated
Oral 20–50 mg/kg
Not proven effect on clinically relevant muscle health
Oral 0.10–0.25 mg/kg (for enalapril)
Control serum creatinine and potassium administration at night to avoid hypotension complaints
Concomitant use with Indomethacin is contra-indicated
Start by 25 % of the recommended dose and increase to full dose in 4 weeks
<12 years:5 μg/kg
>12 years: 2–3 μg/kg
Adults: 1.7 μg/kg
SC 0.05 mg/kg
Early initiation when growth failure persists after optimal control of feeding, electrolytes and rickets
Higher doses of phosphate supplementation may be needed
SC (cfr endocrinology)
Control by blood glucose
Regular control of Hb A1C
immediate release cysteamine bitartrate (Cystagon®)
Start at low dose (1/6 th of optimal dose), gradual increase over 6–8 weeks
delayed release cysteamine bitartrate (Procysbi®)
Start with 80 % of the immediate-release form
Gastrointestinal complaints: add proton pomp inhibitors
Skin lesions (striae, molluscoid tumor at elbows): dose reduction by 25–50 %, control for copper deficiency
Regular dosing of WBC cystine levels (children x4 per year, adults x1-2 per year)b
Corneal cystine crystals
cysteamine eye drops 0.5 %
8–10 time daily
Yearly eye examination
cysteamine eye gel (Cystadrops®)
Proton pump inhibitors omeprazole
<10 kg: 1- mg/kg
10–20 kg: 10–20 mg
>20 kg: 20–40 mg
The current gold standard in the therapeutic monitoring of cystinotic patients is the WBC cystine assay. Theoretically, a more specific and ideal therapeutic monitor would be the direct assessment of the fluctuating lysosomal cystine load in different tissues in response to treatment; however, the invasiveness of tissue samples is prohibitive, especially in children. WBCs offer the second best option, and since cystine accumulates preferentially in polymorphonuclear leucocytes but not in lymphocytes, granulocyte separation is preferred to a mixed leucocyte population ; however, the large blood volume needed, the analyte instability during transportation, the difficult technique and the unavailability of the assay in many countries, all make the WBC cystine assay far from being perfect as a therapeutic monitor. Furthermore, the extremely short life span of polymorphonuclear leucocytes (≈12 h) might not be ideal for the long term follow-up in patients with unstable compliance .
Recently, several non-invasive immunological markers have been proposed to assess the disease activity upon diagnosis and during follow up of cysteamine treatment. The immune system is expected to play a major role in the pathogenesis of nephropathic cystinosis and its rapid progression to ESRD unlike other types of hereditary Fanconi syndromes. Prencipe et al. detected the stimulation of the inflammasome related cytokines: IL-1β, IL-6 and IL-18 in human peripheral mononuclear cells when exposed to cystine crystals, in the plasma of cystinotic patients and in the serum and tissues of Ctns knocked-out mice . On the other hand, we reported the significant elevation of the macrophage marker chitotriosidase in cystinotic patients. Moreover, control human macrophages were potently activated in vitro when exposed to different concentrations of cystine crystals through the significant elevations of TNF-α and chitotriosidase in both supernatant and cell lysate. Chitotriosidase activities were also significantly elevated in the plasma of cystinotic knocked-out versus wild-type mice . These immune based markers could be promising indirect indicators of the disease severity and hence the response to treatment, as the cystine crystal accumulation in cystinosis is the main motive behind their release. Besides, they are much more stable and less technically demanding than the WBC cystine assay. Another possible therapeutic monitor of the cystine crystal load needing further evaluation is the in vivo reflectance confocal microscopy of the skin .
Since it was first reported in early twentieth century, prognosis of cystinosis has improved dramatically, particularly with the advent of cystine-depleting treatment and renal replacement therapy (dialysis and kidney transplantation) in the early 1980s. Consequently more patients are increasingly growing into adulthood instead of succumbing to ESRD by late 1st or early 2nd decade of life. With the increased life expectancy more long-term complications are being recognized and reported, that did not have enough time to evolve in the pediatric age group .
North American Pediatric Renal Transplant Cooperative Study suggests that the outcome of renal transplantation is favorable in patients with a primary diagnosis of cystinosis . A large European observational registry study reported a significant delay in the age of initiation of renal replacement therapy in nephropathic cystinosis patients (0.15 year per calendar year, 95 % confidence interval: 0.1–0.21 year) which wasn’t observable in a matched cohort of non-cystinotic pediatric patients who started renal replacement therapy in the past 2 decades . In an adult patient cohort, renal transplant recipients with cystinosis had a better long-term outcome than other renal transplant recipients. Authors confirmed, by multivariate analysis, that cystinosis is an independent protective factor for graft survival .
Nowadays cystinosis is increasingly being diagnosed at younger age allowing early and adequate initiation of cystine-depleting therapy which significantly prevents, or at least delays, the complications of the disease. That being said, adherence to therapy is critical to improved clinical outcomes. In patients with poor compliance to frequent dosing formulation, the administration of the newly developed delayed-release formulation is likely to improve patient compliance resulting in fewer long-term complications of cystinosis and improved quality of life. Even though cystinosis does not recur in the graft after renal transplantation, yet it continues to progress in other organs and tissues causing complications that may worsen the prognosis, hence the need to continue cysteamine therapy even after kidney transplantation.
Future prospects and unresolved questions
Recent studies linked cystinosin deficiency in cystinosis to other pathophysiologic mechanisms not related to cystine accumulation such as altered vesicle trafficking and impaired mTOR signaling [121–123], thus a better understanding of the pathogenic mechanisms of cystinosis is highly needed to plan and develop more efficient therapeutic targets. Multiple cell and animal cystinotic models have been developed to better understand and characterize the different phenotypic features of the disease. Immortalized cell lines for cystinotic proximal tubular epithelial cells and podocytes have been established and sustained from either biopsy material or exfoliated cells in urine [122–125]. The mouse model for cystinosis has been also available for over a decade now . Although, it can accumulate cystine in most organs, many important phenotypic features like tubulopathy and renal failure were not expressed in the initial model. A second mouse model was later developed on a pure C57BL/6 background that avoided some of the pitfalls of the first one . These cell and animal models provide indispensable tools to study pathologic and molecular mechanisms of the disease. They can be also used to evaluate the in vitro and in vivo responses to experimental new therapeutic drugs and different therapeutic strategies.
With the current rapid advance in the technology of tandem mass spectrometry, the sensitivity of recent machines are almost two to three orders of magnitude the older ones, thus the development of a suitable method for the newborn screening of cystinosis can be applicable in the near future. An interesting approach is the quantification of the deficient protein cystinosin by peptide Immunoaffinity enriched LC-MS/MS analysis. The technology has already been applied for the detection of signature proteins for three primary immunodeficiency diseases: severe combined immunodeficiency (SCID), Wiskott–Aldrich syndrome (WAS), and X-linked agammaglobulinemia (XLA) .
Although, the newly investigated diagnostic markers look promising for the monitoring of disease activity and treatment response [73, 76, 120], longitudinal clinical studies are strongly needed to validate these observations. Laboratory markers as chitotriosidase and interleukins, while being much easier to sample and measure than WBC cystine, are not strictly specific for cystinosis, thus sensitivity and specificity issues need to be handled carefully before determining their utility as therapeutic monitors. On the other hand, the monitoring of the in vivo dermal cystine crystals by confocal microscopy, while being extremely specific for the disease, needs a great deal of experience to operate the instrument and interpret the results. Whether this experience can be available for routine clinical use or not, only the future can tell.
The search for therapeutic substitutes for cysteamine is now strongly ongoing. Adverse effects and compliance issues are still hindering the full capacity of the drug even after the development of the longer acting formulation. The therapeutic focus now is not just cystine depletion, but also how to alleviate other possible harmful pathogenic mechanisms in cystinosis such as inflammation, autophagy and oxidative stress [120, 129, 130]. New promising therapeutics that can target these different disease mechanisms are being currently evaluated in cell and animal models. Hematopoietic stem cell transplantation in humans is another interesting therapeutic option, raising new hopes in finding a cure for cystinosis and further improving long-term clinical outcomes. Being highly successful in the mice model [131, 132], therapeutic human trials are currently being planned but whether it is going to be as successful and safe in humans as in mice, is yet to be determined.
Cystinosis is a systemic disease that needs a multilevel clinical collaboration to rapidly diagnose and properly treat. The current diagnostic and therapeutic regimens made it possible for the transition of most cystinotic patients to adulthood; however, the search for more efficient screening and better therapeutic options through unravelling the basic pathogenic mechanisms of the disease will surely hold the promise to a better future.
Written informed consents were obtained from patients’ parents for the publication of images in this report.
Elena Levtchenko is supported by the Research Foundation - Flanders (F.W.O. Vlaanderen), grant 1801110 N. Mohamed A. Elmonem is supported by ERA-Net E-Rare2 JTC2014. Koenraad R. Veys is supported by the Research Foundation - Flanders (F.W.O. Vlaanderen), grant 11Y5216N.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Abderhalden E. Familiare cystindiathese. Z Physiol Chem. 1903;38:557–61.View ArticleGoogle Scholar
- Lignac GOE. Uber storung des cystinstoffwechsels bei kindern. Deutsch Arch Klin Med. 1924;145:139–50.Google Scholar
- Fanconi G. Die nicht diabetischen glykosurien und hyperglykaemien des aelteren kindes. Jb Kinderheilk. 1931;133:257–300.Google Scholar
- Nesterova G, Gahl WA. Cystinosis: the evolution of a treatable disease. Pediatr Nephrol. 2013;28:51–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Thoene JG, Oshima RG, Crawhall JC, Olson DL, Schneider JA. Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo. J Clin Invest. 1976;58:180–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Liu B, Du H, Rutkowski R, Gartner A, Wang X. LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science. 2012;337:351–4.PubMedPubMed CentralView ArticleGoogle Scholar
- Jézégou A, Llinares E, Anne C, Kieffer-Jaquinod C, O’Regan S, Aupetit J, Chabli A, Sagné C, Debacker C, Chadefaux-Vekemans B, Journet A, André B, Gasnier B. Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy. Proc Natl Acad Sci U S A. 2012;109:E3434–43.PubMedPubMed CentralView ArticleGoogle Scholar
- Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347:111–21.PubMedView ArticleGoogle Scholar
- Cochat P, Cordier B, Lacote C, Said M-H. Cystinosis: Epidemiology in France. In: Broyer M, editor. Cystinosis. Paris: Elsevier; 1999. p. 28–35.Google Scholar
- Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–54.PubMedView ArticleGoogle Scholar
- Manz F, Gretz N. Cystinosis in the Federal Republic of Germany. J Inherit Metab Dis. 1985;8:2–4.PubMedView ArticleGoogle Scholar
- Ebbesen F, Mygind KI, Holck F. Infantile nephropathic cystinosis in Denmark. Danish Med Bull. 1976;23:216–22.PubMedGoogle Scholar
- Hult M, Darin N, von Döbeln U, Månsson JE. Epidemiology of lysosomal storage diseases in Sweden. Acta Paediatr. 2014;103:1258–63.PubMedView ArticleGoogle Scholar
- Bois E, Feingold J, Frenay P, Briard ML. Infantile cystinosis in France: genetics, incidence, geographic distribution. J Med Genet. 1976;13:434–8.PubMedPubMed CentralView ArticleGoogle Scholar
- De Braekeleer M. Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada). Hum Hered. 1991;41:141–6.PubMedView ArticleGoogle Scholar
- Hutchesson AC, Bundey S, Preece MA, Hall SK, Green A. A comparison of disease and gene frequencies of inborn errors of metabolism among different ethnic groups in the West Midlands. UK J Med Genet. 1998;35:366–70.PubMedView ArticleGoogle Scholar
- Elmonem MA, Mahmoud IG, Mehaney DA, Sharaf SA, Hassan SA, Orabi A, Salem F, Girgis MY, El-Badawy A, Abdelwahab M, Salah Z, Soliman NA, Hassan FA, Selim LA. Lysosomal storage disorders in Egyptian children. Ind J Pediatr. 2016. doi:10.1007/s12098-015-2014-x. [Epub ahead of print].Google Scholar
- Levtchenko E, van den Heuvel L, Emma F, Antignac C. Clinical utility gene card for: cystinosis. Eur J Hum Genet. 2014;22(5).
- Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA. CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet. 1998;63:1352–62.PubMedPubMed CentralView ArticleGoogle Scholar
- Soliman NA, Elmonem MA, van den Heuvel L, Abdel Hamid RH, Gamal M, Bongaers I, Marie S, Levtchenko E. Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis. JIMD Rep. 2014;14:87–97.PubMedPubMed CentralView ArticleGoogle Scholar
- Schnaper HW, Cottel J, Merrill S, Marcusson E, Kissane JM, Schackelford GD, So SK, Nelson RD, Cole BR, Smith ML. Early occurence of end-stage renal disease in a patient with infantile cystinosis. J Pediatr. 1992;120:575–8.PubMedView ArticleGoogle Scholar
- Long WS, Seashore MR, Siegel NJ, Bia MJ. Idiopathic Fanconi Syndrome with progressive renal failure: a case report and discussion. Yale J Biol Med. 1990;63:15–28.PubMedPubMed CentralGoogle Scholar
- Brodehl J, Hagge W, Gellisen K. Changes in kidney function in cystinosis. I. Inulin, PAH and electrolyete clearance in various stages of the disease. Ann Paediatr. 1965;205:131–54.PubMedGoogle Scholar
- Baum M. The fanconi syndrome of cystinosis: insights into the pathophysiology. Pediatr Nephrol. 1998;12:492–7.PubMedView ArticleGoogle Scholar
- Roth KS, Foreman JW, Segal S. The Fanconi syndrome and mechanisms of tubular transport dysfunction. Kidney Int. 1981;20:705–16.PubMedView ArticleGoogle Scholar
- Gaide Chevronnay HP, Janssens V, Van Der Smissen P, N’Kuli F, Nevo N, Guiot Y, Levtchenko E, Marbaix E, Pierreux CE, Cherqui S, Antignac C, Courtoy PJ. Time course of pathogenic and adaptation mechanisms in cystinotic mouse kidneys. J Am Soc Nephrol. 2014;25:1256–69.PubMedPubMed CentralView ArticleGoogle Scholar
- Wilmer MJ, Schoeber JP, van den Heuvel LP, Levtchenko EN. Cystinosis: practical tools for diagnosis and treatment. Pediatr Nephrol. 2011;26:205–15.PubMedPubMed CentralView ArticleGoogle Scholar
- O’Regan S, Mongeau JG, Robitaille P. A patient with cystinosis presenting with the features of Bartter syndrome. Acta Paediatr Belg. 1980;33:51–2.PubMedGoogle Scholar
- Ozkan B, Cayir A, Kosan C, Alp H. Cystinosis presenting with findings of barter syndrome. J Clin Res Pediatr Endocrinol. 2011;3:101–4.PubMedPubMed CentralView ArticleGoogle Scholar
- Gahl WA, Reed GF, Thoene JG, Schulman JD, Rizzo WB, Jonas AJ. Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med. 1987;316:971–7.PubMedView ArticleGoogle Scholar
- Besouw M, Levtchenko E. Growth retardation in children with cystinosis. Minerva Pediatr. 2010;62:307–14.PubMedGoogle Scholar
- Theodoropoulos DS, Shawker TH, Heinrichs C, Gahl WA. Medullary nephrocalcinosis in nephropathiccystinosis. Pediatr Nephrol. 1995;9:412–8.PubMedView ArticleGoogle Scholar
- Betend B, Chatelain P, David L, François R. Treatment of rickets caused by infantile cystinosis using 1 alpha-hydroxy vitamin D. Arch Fr Pediatr. 1982;39:615–8.PubMedGoogle Scholar
- Wilmer MJ, Christensen EI, van den Heuvel LP, Monnens LA, Levtchenko EN. Urinary protein excretion pattern and renal expression of megalin and cubilin in nephropathic cystinosis. Am J Kidney Dis. 2008;51:893–903.PubMedView ArticleGoogle Scholar
- Gretz N, Manz F, Augustin R, Barrat TM, Bender-Götze C, Brandis M. Survival time in cystinosis: a collaborative study. Proc Eur Dial Transplant Assoc. 1983;19:582–9.PubMedGoogle Scholar
- Brodin Sartorius A, Tete MJ, Niaudet P, Antignac C, Guest G, Ottolenghi C, Charbit M, Moyse D, Legendre C, Lesavre P, Cochat P, Servais A. Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults. Kidney Int. 2012;81:179–89.PubMedView ArticleGoogle Scholar
- Middleton R, Bradbury M, Webb N, O’Donoghue D, van’t Hoff W. Cystinosis. A clinico-pathological conference. “from toddlers to twenties and beyond” adult-paediatric nephrology interface meeting, Manchester 2001. Nephrol Dial Transplant. 2003;18:2492–5.PubMedView ArticleGoogle Scholar
- Servais A, Morinière V, Grünfeld JP, Noël LH, Goujon JM, Chadefaux-Vekemans B, Antignac C. Late-onset nephropathic cystinosis: clinical presentation, outcome, and genotyping. Clin J Am Soc Nephrol. 2008;3:27–35.PubMedPubMed CentralView ArticleGoogle Scholar
- Anikster Y, Lucero C, Guo J, Huizing M, Shotelersuk V, Bernardini I, McDowell G, Iwata F, Kaiser-Kupfer MI, Jaffe R, Thoene J, Schneider JA, Gahl WA. Ocular non-nephropathic cystinosis: clinical, biochemical, and molecular correlations. Pediatr Res. 2000;47:17–23.PubMedView ArticleGoogle Scholar
- Nesterova G, Gahl WA. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol. 2008;23:863–7.PubMedView ArticleGoogle Scholar
- Kaiser-Kupfer MI, Caruso RC, Minkler DS, Gahl WA. Long-term ocular manifestations in nephropathic cystinosis. Arch Ophtalmol. 1986;104:706–11.View ArticleGoogle Scholar
- Tsilou ET, Rubin BI, Reed GF, Iwata F, Gahl W, Kaiser-Kupfer MI. Age-related prevalence of anterior segment complications in patients with infantile nephropathic cystinosis. Cornea. 2006;21:173–6.View ArticleGoogle Scholar
- Tsilou ET, Rubin BI, Reed G, Caruso RS, Iwata F, Balog J, Gahl WA, Kaiser-Kupfer MI. Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy. Ophtalmology. 2006;113:1002–9.View ArticleGoogle Scholar
- Gahl WA, Kuehl EM, Iwata F, Lindblad A, Kaiser-Kupfer MI. Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eye drops. Mol Genet Metab. 2000;71:100–20.PubMedView ArticleGoogle Scholar
- Chan AM, Lynch MJG, Bailey JD, Ezrin C, Fraser D. Hypothyroidism in cystinosis. A clinical, endocrinologic and histologic study involving sixteen patients with cystinosis. Am J Med. 1970;48:678–92.PubMedView ArticleGoogle Scholar
- Grünebaum M, Lebowitz RL. Hypothyroidism in cystinosis. Am J Roentgenol. 1977;129:629–30.View ArticleGoogle Scholar
- Gaide Chevronnay HP, Janssens V, Van Der Smissen P, Liao XH, Abid Y, Nevo N, Antignac C, Refetoff S, Cherqui S, Pierreux CE, Courtoy PJ. A mouse model suggests two mechanisms for thyroid alterations in infantile cystinosis: decreased thyroglobulin synthesis due to endoplasmic reticulum stress/unfolded protein response and impaired lysosomal processing. Endocrinology. 2015;156:2349–64.PubMedView ArticleGoogle Scholar
- Gahl WA, Schneider JA, Thoene JG, Chesney R. The course of nephropathic cystinosis after age 10 years. J Pediatr. 1986;109:605–8.PubMedView ArticleGoogle Scholar
- Fivush B, Green OC, Porter CC, Balfe JW, O’Regan S, Gahl WA. Pancreatic endocrine insufficiency in post-transplant cystinosis. Am J Dis Child. 1987;141:1087–9.PubMedGoogle Scholar
- Filler G, Amendt P, von Bredow MA, Rohde W, Ehrich JH. Slowly deteriorating insulin secretion and C-peptide production characterizes diabetes mellitus in infantile cystinosis. Eur J Pediatr. 1998;157:738–42.PubMedView ArticleGoogle Scholar
- Fivush B, Flick JA, Gahl WA. Pancreatic exocrine insufficiency in a patient with nephropathic cystinosis. J Pediatr. 1998;112:49–51.View ArticleGoogle Scholar
- Winkler L, Offner G, Krull F, Brodehl J. Growth and pubertal development in nephropathic cystinosis. Eur J Pediatr. 1993;152:244–9.PubMedView ArticleGoogle Scholar
- Chik CL, Friedman A, Merriam GR, Gahl WA. Pituitary testicular function in nephropathiccystinosis. Ann Intern Med. 1993;119:568–75.PubMedView ArticleGoogle Scholar
- Besouw MT, Kremer JA, Janssen MC, Levtchenko EN. Fertility status in male cystinosis patients treated with cysteamine. Fertil Steril. 2010;93:1880–3.PubMedView ArticleGoogle Scholar
- Reiss RE, Kuwabara T, Smith ML, Gahl WA. Succesful pregnancy despite placental cystine crystals in a woman with nephropathic cystinosis. N Engl J Med. 1988;319:223–6.PubMedView ArticleGoogle Scholar
- Fink JK, Brouwers P, Barton N, Malekzadeh MH, Sato S, Hill S, Cohen WE, Fivush B, Gahl WA. Neurologic complications in long-standing nephropathic cystinosis. Arch Neurol. 1989;46:543–8.PubMedView ArticleGoogle Scholar
- Broyer M, Tete MJ, Guest G, Bertheleme JP, Labrousse F, Poisson M. Clinical polymorphism of cystinosis encephalopathy. Results of treatment with cysteamine. J Inherit Metab Dis. 1996;19:65–75.PubMedView ArticleGoogle Scholar
- Nichols SL, Press GA, Schneider JA, Trauner DA. Cortical atrophy and cognitive performance in infantile nephropathic cystinosis. Pediatr Neurol. 1990;6:379–81.PubMedView ArticleGoogle Scholar
- Trauner DA, Chase C, Scheller J, Katz B, Schneider JA. Neurologic and cognitive deficits in children with cystinosis. J Pediatr. 1988;112:912–4.PubMedView ArticleGoogle Scholar
- Dogulu CF, Tsilou E, Rubin B, Fitsgibbon EJ, Kaiser-Kupfer MI, Rennert OM, Gahl WA. Idiopathic Intracranial hypertension in cystinosis. J Pediatr. 2004;145:673–8.PubMedView ArticleGoogle Scholar
- Delgado G, Schatz A, Nichols S, Appelbaum M, Trauner D. Behavioral profiles of children with infantile nephropathic cystinosis. Dev Med Child Neurol. 2004;47:403–7.View ArticleGoogle Scholar
- Besouw MT, Hulstijn-Dirkmaat GM, van der Rijken RE, Cornelissen EA, van Dael CM, Vande Walle J, Lilien MR, Levtchenko EN. Neurocognitive functioning in school-aged cystinosis patients. J Inherit Metab Dis. 2010;33:787–93.PubMedPubMed CentralView ArticleGoogle Scholar
- Bava S, Theilmann RJ, Sach M, May SJ, Frank LR, Hesselink JR, Vu D, Trauner DA. Developmental changes in cerebral white matter microstructure in a disorder of lysosomal storage. Cortex. 2010;46:206–16.PubMedPubMed CentralView ArticleGoogle Scholar
- Gahl WA, Dalakas MC, Charnas L, Chen KT, Pezeshkpour GH, Kuwabara T. Myopathy and cystine storage in muscles in a patient with nephropathic cystinosis. N Engl J Med. 1988;319:1461–4.PubMedView ArticleGoogle Scholar
- Vester U, Schubeter M, Offner G, Brodehl J. Distal myopathy in nephropathic cystinosis. Pediatr Nephrol. 2000;14:36–8.PubMedView ArticleGoogle Scholar
- Anikster Y, Lacbawan F, Brantly M, Gochuico BL, Avila NA, Travis W, Gahl WA. Pulmonary dysfunction in adults with nephropathic cystinosis. Chest. 2001;119:394–401.PubMedView ArticleGoogle Scholar
- Sonies BC, Almajid P, Kleta R, Bernardini I, Gahl WA. Swallowing dysfunction in 101 patients with nephropathic cystinosis – benefit of long-term cysteamine therapy. Medicine. 2005;84:137–46.PubMedView ArticleGoogle Scholar
- Guillet G, Sassolas B, Fromentoux S, Gobin E, Leroy JP. Skin storage of cystine and premature skin ageing in cystinosis. Lancet. 1998;352:1444–5.PubMedView ArticleGoogle Scholar
- Chiaverini C, Sillard L, Flori E, Ito S, Briganti S, Wakamatsu K, Fontas E, Berard E, Cailliez M, Cochat P, Foulard M, Guest G, Niaudet P, Picardo M, Bernard FX, Antignac C, Ortonne JP, Ballotti R. Cystinosin is a melanosomal protein that regulates melanin synthesis. FASEB J. 2012;26:3779–89.PubMedView ArticleGoogle Scholar
- Oshima RG, Willis RC, Furlong CE, Schneider JA. Binding assays for amino acids. The utilization of a cystine binding protein from Escherichia coli for the determination of acid-soluble cystine in small physiological samples. J Biol Chem. 1974;249:6033–9.PubMedGoogle Scholar
- de Graaf-Hess A, Trijbels F, Blom H. New method for determining cystine in leukocytes and fibroblasts. Clin Chem. 1999;45:2224–8.PubMedGoogle Scholar
- Chabli A, Aupetit J, Raehm M, Ricquier D, Chadefaux-Vekemans B. Measurement of cystine in granulocytes using liquid chromatography-tandem mass spectrometry. Clin Biochem. 2007;40:692–8.PubMedView ArticleGoogle Scholar
- Elmonem MA, Makar SH, van den Heuvel L, Abdelaziz H, Abdelrahman SM, Bossuyt X, Janssen MC, Cornelissen EA, Lefeber DJ, Joosten LA, Nabhan MM, Arcolino FO, Hassan FA, Gaide Chevronnay HP, Soliman NA, Levtchenko E. Clinical utility of chitotriosidase enzyme activity in nephropathic cystinosis. Orphanet J Rare Dis. 2014;9:155.PubMedPubMed CentralView ArticleGoogle Scholar
- Taranta A, Wilmer MJ, van den Heuvel LP, Bencivenga P, Bellomo F, Levtchenko EN, Emma F. Analysis of CTNS gene transcripts in nephropathic cystinosis. Pediatr Nephrol. 2010;25:1263–7.PubMedPubMed CentralView ArticleGoogle Scholar
- Soliman NA, El-Baroudy R, Rizk A, Bazaraa H, Younan A. Nephropathic cystinosis in children: An overlooked disease. Saudi J Kidney Dis Transpl. 2009;20:436–42.PubMedGoogle Scholar
- Chiavérini C, Kang HY, Sillard L, Berard E, Niaudet P, Guest G, Cailliez M, Bahadoran P, Lacour JP, Ballotti R, Ortonne JP. In vivo reflectance confocal microscopy of the skin: a noninvasive means of assessing body cystine accumulation in infantile cystinosis. J Am Acad Dermatol. 2013;68:e111–6.PubMedView ArticleGoogle Scholar
- Besouw MT, Van Dyck M, Cassiman D, Claes KJ, Levtchenko EN. Management dilemmas in pediatric nephrology: Cystinosis. Pediatr Nephrol. 2015. doi:10.1007/s00467-015-3117-3. [Epub ahead of print].PubMedGoogle Scholar
- Wamelink MM, Struys EA, Jansen EE, Blom HJ, Vilboux T, Gahl WA, Kömhoff M, Jakobs C, Levtchenko EN. Elevated concentrations of sedoheptulose in bloodspots of patients with cystinosis caused by the 57-kb deletion: implications for diagnostics and neonatal screening. Mol Genet Metab. 2011;102:339–42.PubMedView ArticleGoogle Scholar
- Heil SG, Levtchenko E, Monnens LA, Trijbels FJ, Van der Put NM, Blom HJ. The molecular basis of Dutch infantile nephropathic cystinosis. Nephron. 2001;89:50–5.PubMedView ArticleGoogle Scholar
- Kiehntopf M, Varga RE, Koch HG, Beetz C. A homemade MLPA assay detects known CTNS mutations and identifies a novel deletion in a previously unresolved cystinosis family. Gene. 2012;495:89–92.PubMedView ArticleGoogle Scholar
- Bendavid C, Kleta R, Long R, Ouspenskaia M, Muenke M, Haddad BR, Gahl WA. FISH diagnosis of the common 57-kb deletion in CTNS causing cystinosis. Hum Genet. 2004;115:510–4.PubMedView ArticleGoogle Scholar
- States B, Blazer B, Harris D, Segal S. Prenatal diagnosis of cystinosis. J Pediatr. 1975;87:558–62.PubMedView ArticleGoogle Scholar
- Jackson M, Young E. Prenatal diagnosis of cystinosis by quantitative measurement of cystine in chorionic villi and cultured cells. Prenat Diagn. 2005;25:1045–7.PubMedView ArticleGoogle Scholar
- Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wühl E, Niaudet P, Van’t Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014;29:iv87–94.PubMedPubMed CentralView ArticleGoogle Scholar
- Loirat C. Symptomatic therapy. In: Broyer M, editors. Cystinosis, 1st edn Elsevier; Paris: 1999.pp.97–102.
- Cochat P, Pichault V, Bacchetta J, Dubourg L, Sabot JF, Saban C, Daudon M, Liutkus A. Nephrolithiasis related to inborn metabolic diseases. Pediatr Nephrol. 2010;25:415–24.PubMedPubMed CentralView ArticleGoogle Scholar
- Gahl WA, Bernardini I, Dalakas M, Rizzo WB, Harper GS, Hoeg JM, Hurko O, Bernar J. Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome. J Clin Invest. 1988;81:549–60.PubMedPubMed CentralView ArticleGoogle Scholar
- Gahl WA, Bernardini IM, Dalakas MC, Markello TC, Krasnewich DM, Charnas LR. Muscle carnitine repletion by long-term carnitine supplementation in nephropathic cystinosis. Pediatr Res. 1993;34:115–9.PubMedView ArticleGoogle Scholar
- Elenberg E, Norling LL, Kleinman RE, Ingelfinger JR. Feeding problems in cystinosis. Pediatr Nephrol. 1998;12:365–70.PubMedView ArticleGoogle Scholar
- Besouw MT, Van Dyck M, Francois I, Van Hoyweghen E, Levtchenko EN. Detailed studies of growth hormone secretion in cystinosis patients. Pediatr Nephrol. 2012;27:2123–7.PubMedView ArticleGoogle Scholar
- Greco M, Brugnara M, Zaffanello M, Taranta A, Pastore A, Emma F. Long-term outcome of nephropathic cystinosis: a 20-year single-center experience. Pediatr Nephrol. 2010;25:2459–67.PubMedView ArticleGoogle Scholar
- Levtchenko E, Blom H, Wilmer M, van den Heuvel L, Monnens L. ACE inhibitor enalapril diminishes albuminuria in patients with cystinosis. Clin Nephrol. 2003;60:386–9.PubMedView ArticleGoogle Scholar
- Spear GS, Gubler MC, Habib R, Broyer M. Renal allografts in cystinosis and mesangial demography. Clin Nephrol. 1989;32:256–61.PubMedGoogle Scholar
- Kashtan CE, McEnery PT, Tejani A, Stablein DM. Renal allograft survival according to primary diagnosis: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol. 1995;9:679–84.PubMedView ArticleGoogle Scholar
- Rigden SP. Data from the ERA-EDTA registry. In: Broyer M, editor. Cystinosis. 1st ed. Amsterdam: Elsevier; 1999. p. 20–7.Google Scholar
- Cohen C, Charbit M, Chadefaux-Vekemans B, Giral M, Garrigue V, Kessler M, Antoine C, Snanoudj R, Niaudet P, Kreis H, Legendre C, Servais A. Excellent long-term outcome of renal transplantation in cystinosis patients. Orphanet J Rare Dis. 2015;10:90.PubMedPubMed CentralView ArticleGoogle Scholar
- Ehrich JH, Brodehl J, Byrd DI, Hossfeld S, Hoyer PF, Leipert KP, Offner G, Wolff G. Renal transplantation in 22 children with nephropathic cystinosis. Pediatr Nephrol. 1991;5:708–14.PubMedView ArticleGoogle Scholar
- Schneider JA, Clark KF, Greene AA, Reisch JS, Markello TC, Gahl WA, Thoene JG, Noonan PK, Berry KA. Recent advances in the treatment of cystinosis. J Inherit Metab Dis. 1995;18:387–97.PubMedView ArticleGoogle Scholar
- Markello TC, Bernardini IM, Gahl WA. Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med. 1993;328:1157–62.PubMedView ArticleGoogle Scholar
- Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med. 2007;147:242–50.PubMedView ArticleGoogle Scholar
- Van Stralen KJ, Emma F, Jager KJ, Verrina E, Schaefer F, Laube GF, Lewis MA, Levtchenko EN. Improvement in the renal prognosis in nephropathic cystinosis. Clin J Am Soc Nephrol. 2011;6:2485–91.PubMedPubMed CentralView ArticleGoogle Scholar
- Kleta R, Bernardini I, Ueda M, Varade WS, Phrnphutkul C, Krasnewich D, Gahl WA. Long-term follow-up of well-treated nephropathic cystinosis patients. J Pediatr. 2004;145:555–60.PubMedView ArticleGoogle Scholar
- Kimonis VE, Troendle J, Rose SR, Ynag ML, Markello TC, Gahl WA. Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis. J Clin Endocrinol Metab. 1995;80:3257–61.PubMedGoogle Scholar
- Van’t Hoff WG, Gretz N. The treatment of cystinosis with cysteamine and phosphocysteamine in the United Kingdom and Eire. Pediatr Nephrol. 1995;9:685–9.View ArticleGoogle Scholar
- Labbé A, Baudouin C, Deschênes G, Loirat C, Charbit M, Guest G, Niaudet P. A new gel formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis: the Cystadrops OCT-1 study. Mol Genet Metab. 2014;111:314–20.PubMedView ArticleGoogle Scholar
- Nesterova G, Williams C, Bernardini I, Gahl WA. Cystinosis: renal glomerular and renal tubular function in relation to compliance with cystine-depleting therapy. Pediatr Nephrol. 2015;30:945–51.PubMedView ArticleGoogle Scholar
- Wenner WJ, Murphy JL. The effects of cysteamine on the upper gastrointestinal tract of children with cystinosis. Pediatr Nephrol. 1997;11:600–3.PubMedView ArticleGoogle Scholar
- Dohil R, Newbury RO, Sellers ZM, Deutsch R, Schneider JA. The evaluation and treatment of gastrointestinal disease in children with cystinosis receiving cysteamine. J Pediatr. 2003;143:224–30.PubMedView ArticleGoogle Scholar
- Dohil R, Fidler M, Barshop BA, Gangoiti J, Deutsch R, Martin M, Schneider JA. Understanding intestinal cysteamine bitartrate absorption. J Pediatr. 2006;148:764–9.PubMedView ArticleGoogle Scholar
- Dohil R, Fidler M, Barshop B, Newbury R, Sellers Z, Deutsch R, Schneider J. Esomeprazole therapy for gastric acid hypersecretion in children with cystinosis. Pediatr Nephrol. 2005;20:1786–93.PubMedView ArticleGoogle Scholar
- Besouw M, Blom H, Tangerman A, de Graaf-Hess A, Levtchenko E. The origin of halitosis in cystinotic patients due to cysteamine treatment. Mol Genet Metab. 2007;91:228–33.PubMedView ArticleGoogle Scholar
- Ivanova E, De Leo MG, De Matteis MA, Levtchenko E. Cystinosis: clinical presentation, pathogenesis and treatment. Pediatr Endocrinol Rev. 2014;12 Suppl 1:176–84.PubMedGoogle Scholar
- Besouw MT, Bowker R, Dutertre JP, Emma F, Gahl WA, Greco M, Lilien MR, McKiernan J, Nobili F, Schneider JA, Skovby F, van den Heuvel LP, Hoff WG Van’t, Levtchenko EN. Cysteamine toxicity in patients with cystinosis. J Pediatr. 2011;159:1004–11.
- Corden BJ, Schulman JD, Schneider JA, Thoene JG. Adverse reactions to oral cysteamine use in nephropathic cystinosis. Dev Pharmacol Ther. 1981;3:25–30.PubMedGoogle Scholar
- Beckman DA, Mullin JJ, Assadi FK. Developmental toxicity of cysteamine in the rat: effects on embryo-fetal development. Teratology. 1998;58:96–102.PubMedView ArticleGoogle Scholar
- Assadi FK, Mullin JJ, Beckman DA. Evaluation of the reproductive and developmental safety of cysteamine in the rat: effects on female reproduction and early embryonic development. Teratology. 1998;58:88–95.PubMedView ArticleGoogle Scholar
- Levtchenko EN, van Dael CM, de Graaf-Hess AC, Wilmer MJ, van den Heuvel LP, Monnens LA, Blom HJ. Strict cysteamine dose regimen is required to prevent nocturnal cystine accumulation in cystinosis. Pediatr Nephrol. 2006;21:110–3.PubMedView ArticleGoogle Scholar
- Dohil R, Fidler M, Gangoiti JA, Kaskel F, Schneider JA, Barshop BA. Twice-daily cysteamine bitartrate therapy for children with cystinosis. J Pediatr. 2010;156:71–5.PubMedView ArticleGoogle Scholar
- Levtchenko E, de Graaf-Hess A, Wilmer M, van den Heuvel L, Monnens L, Blom H. Comparison of cystine determination in mixed leukocytes vs polymorphonuclear leukocytes for diagnosis of cystinosis and monitoring of cysteamine therapy. Clin Chem. 2004;50:1686–8.PubMedView ArticleGoogle Scholar
- Prencipe G, Caiello I, Cherqui S, Whisenant T, Petrini S, Emma F, De Benedetti F. Inflammasome activation by cystine crystals: implications for the pathogenesis of cystinosis. J Am Soc Nephrol. 2014;25:1163–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Andrzejewska Z, Nevo N, Thomas L, Chhuon C, Bailleux A, Chauvet V, Courtoy PJ, Chol M, Guerrera IC, Antignac C. Cystinosin is a Component of the Vacuolar H + −ATPase-Ragulator-Rag Complex Controlling Mammalian Target of Rapamycin Complex 1 Signaling. J Am Soc Nephrol. 2015 [Epub ahead of print].
- Ivanova EA, De Leo MG, Van Den Heuvel L, Pastore A, Dijkman H, De Matteis MA, Levtchenko EN. Endo-lysosomal dysfunction in human proximal tubular epithelial cells deficient for lysosomal cystine transporter cystinosin. PLoS One. 2015;10, e0120998.PubMedPubMed CentralView ArticleGoogle Scholar
- 123- Ivanova EA, van den Heuvel LP, Elmonem MA, De Smedt H, Missiaen L, Pastore A, Mekahli D, Bultynck G, Levtchenko E. Altered mTOR signalling in nephropathic cystinosis. J Inherit Metab Dis. 2016 [In press].
- Jansen J, Schophuizen CMS, Wilmer MJ, Lahham SH, Mutsaers HA, Wetzels JF, Bank RA, van den Heuvel LP, Hoenderop JG, Masereeuw R. A morphological and functional comparison of proximal tubule cell lines established from human urine and kidney tissue. Exp Cell Res. 2014;323:87–99.PubMedView ArticleGoogle Scholar
- Oliveira Arcolino F, Tort Piella A, Papadimitriou E, Bussolati B, Antonie DJ, Murray P, van den Heuvel L, Levtchenko E. Human Urine as a Noninvasive Source of Kidney Cells. Stem Cells Int. 2015;2015:362562.PubMedPubMed CentralView ArticleGoogle Scholar
- Cherqui S, Kalatzis V, Forestier L, Poras I, Antignac C. Identification and characterisation of the murine homologue of the gene responsible for cystinosis. Ctns BMC Genomics. 2000;1:2.PubMedView ArticleGoogle Scholar
- Nevo N, Chol M, Bailleux A, Kalatzis V, Morisset L, Devuyst O, Gubler MC, Antignac C. Renal phenotype of the cystinosis mouse model is dependent upon genetic background. Nephrol Dial Transplant. 2010;25:1059–66.PubMedView ArticleGoogle Scholar
- Kerfoot SA, Jung S, Golob K, Torgerson TR, Hahn SH. Tryptic peptide screening for primary immunodeficiency disease by LC/MS-MS. Proteomics Clin Appl. 2012;6:394–402.PubMedPubMed CentralView ArticleGoogle Scholar
- Sansanwal P, Sarwal MM. Abnormal mitochondrial autophagy in nephropathic cystinosis. Autophagy. 2010;6:971–3.PubMedPubMed CentralView ArticleGoogle Scholar
- Galarreta CI, Forbes MS, Thornhill BA, Antignac C, Gubler MC, Nevo N, Murphy MP, Chevalier RL. The swan-neck lesion: proximal tubular adaptation to oxidative stress in nephropathic cystinosis. Am J Physiol Renal Physiol. 2015;308:F1155–66.PubMedView ArticleGoogle Scholar
- Syres K, Harrison F, Tadlock M, Jester JV, Simpson J, Roy S, Salomon DR, Cherqui S. Successful treatment of the murine model of cystinosis using bone marrow cell transplantation. Blood. 2009;114:2542–52.PubMedView ArticleGoogle Scholar
- Harrison F, Yeagy BA, Rocca CJ, Kohn DB, Salomon DR, Cherqui S. Hematopoietic stem cell gene therapy for the multisystemic lysosomal storage disorder cystinosis. Mol Ther. 2013;21:433–44.PubMedPubMed CentralView ArticleGoogle Scholar