Cystinosis

INTRODUCTION — Cystinosis is a lysosomal storage disease characterized by an intracellular accumulation of cystine in different organs and tissues, leading to potentially severe organ dysfunction.

The diagnosis, treatment, and outcome of cystinosis and the clinical features of the three different forms of cystinosis will be discussed here.

DEFINITION

●Cystinosis is a lysosomal storage disease characterized by an intracellular accumulation of cystine in different organs and tissues, leading to potentially severe organ dysfunction.

Three forms of cystinosis have been described primarily based on age of presentation and severity of phenotype:

•Infantile (nephropathic) form (MIM #219800). (See 'Infantile cystinosis' below.)

•Late-onset (juvenile) form (MIM #219900). (See 'Late-onset (juvenile) cystinosis' below.)

•Adult (benign) form (MIM #219750). (See 'Adult (benign or ocular) cystinosis' below.)

●Cystinuria is a different disorder from cystinosis. It is a genetic disorder with impaired proximal tubular reabsorption of filtered cystine, resulting in increased urinary cystine excretion and cystine kidney stones. (See "Cystinuria and cystine stones".)

EPIDEMIOLOGY — Infantile cystinosis, also referred to as nephropathic cystinosis, is the most common form of cystinosis and is estimated to affect 1 of every 100,000 to 200,000 children [1-4]. There appears to be a higher incidence in some regions, such as Brittany in France or Saguenay-Lac-Saint-Jean, Quebec in Canada, [5-7].

PATHOGENESIS — Cystine is the oxidized dimer form of the amino acid cysteine and is derived from protein degradation within the lysosomes of cells. Free cystine is normally transported through the lysosomal membrane to the cytosol where it is reutilized after its transformation to cysteine. In cystinosis, cystine accumulates inside the lysosomes because of a defect in the gene that encodes cystinosin, the protein that transports cystine across the lysosomal membrane [8-13]. Cystine is poorly soluble and forms crystals as its concentration increases.

Cell and tissue injury — It is not clear how cystine accumulation results in cellular dysfunction [8]. The following observations have been made:

●Cystine depletes the glutathione cell pool, thereby favoring oxidative stress and apoptosis [14,15].

●Impaired chaperone-mediated autophagy contributes to cell dysfunction in cystinosis [16].

●Overexpression of intracellular clusterin was observed, which may contribute to cell stress, cell injury, and apoptosis [17].

●Cystinosin deficiency results in a highly pathologic podocyte phenotype with reduced cell adhesion and hypermotility associated with enhanced AKT1 and AKT2 phosphorylation [18].

In addition, studies have focused on specific organ damage:

●Kidney

•Cysteinylation of protein kinase delta by accumulated cystine increases apoptosis of the cystine-laden renal proximal tubular cell, which causes tubular dysfunction [19].

•Cystine accumulation in proximal tubular cells in vitro is associated with ATP depletion and inhibition of Na⁺ dependent transporters [20,21].

•In the infantile form, histologic examination of cystinotic kidneys shows nonspecific tubular and glomerular lesions. The proximal and distal tubules are dilated or atrophic and vacuoles may be seen in the tubular cells. Interstitial fibrosis and glomerulosclerosis are seen in advanced disease

●Brain – Inhibition of adenylate cyclase activity by cystine in rat brain is prevented by cysteamine [22]. In addition, cellular cystine accumulation may inhibit pyruvate kinase and creatine kinase activity in rat brain or pig retina [23-25].

Genetics — Cystinosis is transmitted as an autosomal recessive trait. Multiple observations indicate that the same gene is involved in all forms of the disease [26]. Both the infantile and juvenile forms can occur in a given family. In addition, complementation studies using fibroblasts from patients' different types of cystinosis have shown the absence of correction of the metabolic defect [27]. It therefore appears that there is no genetic heterogeneity and that the differences in the clinical manifestations result from variants occurring in a single gene.

The gene for cystinosis has been mapped to chromosome 17p13 [28]. The gene, CTNS, consists of 12 exons and encodes for a 367 amino acid lysosomal membrane protein, named cystinosin [28-30]. It appears to be a novel hydrogen ion-driven transporter that is responsible for exporting cystine from lysosomes [31].

More than 140 mutations in the first 10 exons and in the promoter of the gene have been described in patients with cystinosis, with the clinical phenotype segregating with specific defects [8,32-35].

Infantile form — Large deletions in CTNS, as well as other mutations that would result in missense or in-frame deletions, are associated with infantile cystinosis, the most severe phenotype [33]. These abnormalities result in the loss of adequate function of the cystinosin protein, including no protein expression with some mutations.

A 65 kb deletion is the most frequent mutation found in the homozygous state and is observed in nearly one-third of all patients with cystinosis. This deletion is present in either the homozygous or the heterozygous state in approximately 75 percent of patients of European origin [36], thus allowing a rapid polymerase chain reaction (PCR)-based diagnostic test for this disease (see 'Diagnosis' below).

In some cases, the adjacent gene CARKL, which encodes the enzyme sedoheptulokinase, is also affected. This explains why some patients have elevated serum and urinary concentrations of sedoheptulose [37].

Late-onset (juvenile) form — Intermediate cystinosis is more indolent than the infantile form of cystinosis. Affected patients have a variant known to cause infantile disease in one allele and a relatively less clinically severe variant in the other or they have a relatively less severe variant in both alleles [33,38].

Adult cystinosis — Adult or benign (or ocular nonnephropathic) cystinosis is characterized by the presence of corneal crystals and photophobia and less often kidney disease [39]. Similar to intermediate cystinosis, this form may be due to the inheritance of different abnormal alleles, including the presence of a severe plus a mild variant [34].

INFANTILE CYSTINOSIS

Presentation — Cystinosis is characterized by both kidney and extrarenal symptoms that present after birth [40]. Affected infants typically present between three and six months of age with signs and symptoms due to renal tubular dysfunction. These include polyuria, polydipsia, poor weight gain, and acute episodes of hypovolemia [41]. In addition, physical findings of rickets may be present (eg, swelling of the wrists and frontal bossing).

Renal manifestations — Kidney manifestations are due to impaired proximal tubular reabsorptive capacity, leading to the varied manifestations of de Toni-Debré-Fanconi syndrome (tubular proteinuria with massive excretion of beta-2 microglobulin and lysozyme, glycosuria, phosphaturia, and aminoaciduria). (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Fanconi syndrome'.)

●Sodium wasting and severe urinary concentrating defect result in polyuria (reaching 2 to 3 L/day), polydipsia, and acute dehydration episodes [41].

●Excessive losses of potassium, sodium, and bicarbonate lead to hypokalemia, hyponatremia, and metabolic acidosis.

●Phosphopenic rickets (manifested by swelling of the wrists, frontal bossing, and genu valgum) is often noted at presentation due in part to renal phosphate wasting and hypophosphatemia (see "Overview of rickets in children") [42].

●Hypouricemia is constant and hypercalciuria may lead to nephrocalcinosis [43]. (See "Nephrocalcinosis", section on 'High urine calcium without hypercalcemia'.)

The tubular losses gradually become less prominent after six years of age due to a progressive decline in the glomerular filtration rate (GFR). End-stage kidney disease (ESKD) typically occurs before age 10 in the absence of cysteamine treatment.

Extrarenal manifestations — The extrarenal symptoms are due to the intracellular accumulation of cystine in different tissues and organs and typically present later than the renal manifestations [40].

●General appearance – On general inspection, many affected children have blond hair and white skin, which may be explained by the role of cystinosin in melanogenesis [44].

●Poor growth – Poor growth is a major feature of cystinotic patients, often accompanied by a delay in bone age when compared with chronologic age. The mean adult height is typically only 54 inches (136.5 cm) in males and 49 inches (124 cm) in females. Early therapy with fluid and electrolyte supplements, indomethacin, cysteamine, and growth hormone leads to improved growth outcomes.

●Ocular involvement – The eyes are involved early in the course of the disease, as cystine deposits in the cornea and the conjunctiva can be seen on slit-lamp examination from the age of 12 months. These deposits are responsible for photophobia, watering, and blepharospasm. Irregular and peripheral depigmentation of the retina is also an early finding. Visual impairment may occur later, in children older than 10 years [45,46]. Hemorrhagic retinopathy may also be a complication of this disorder [40].

●Enlarged liver and spleen – Hepatomegaly, resulting from enlarged Kupffer cells with cystine crystals, occurs in 40 percent of patients and may lead to portal hypertension. Portal hypertension leads to splenomegaly with enlarged cells in the red pulp.

●Hypothyroidism – Hypothyroidism usually appears between 8 and 12 years of age and develops in approximately one-half of untreated patients [47]. It can be detected by the demonstration of high plasma thyroid-stimulating hormone (TSH) levels, which occur before the thyroxine concentration begins to fall [48]. Symptoms of hypothyroidism are uncommon, but this problem may contribute to the growth impairment.

●Diabetes – Insulin-dependent diabetes has been reported, primarily in cystinotic patients on peritoneal dialysis or after kidney transplantation when high doses of corticosteroids are given to treat acute rejection [49]. The hyperglycemia is usually transient, although a few patients require chronic insulin therapy [50]. Cystinotic patients show a slow, progressive loss of insulin production and C-peptide production leading to a 50 percent risk of developing glucose intolerance by the age of 18 years thought to be due cystine accumulation in beta cells [51]. Exocrine pancreatic insufficiency with steatorrhea has been reported in one patient [52].

●Muscular weakness – Muscular weakness is seen in affected patients and is due initially to hypokalemia and to carnitine deficiency. Older children and adults may develop a myopathy potentially leading to a severe disability with generalized muscle atrophy and weakness, especially the distal muscles of all limbs [53-55].

Pulmonary dysfunction is correlated with the severity of myopathy [56,57].

Pharyngeal and oral dysfunction, which may also cause voice changes, is often observed and may contribute to aspiration pneumonia [54,58,59]. Swallowing dysfunction appears to correct with cysteamine treatment [60]. A simple, noninvasive test, Test of Mastication and Swallowing Solids (TOMASS), can be performed to detect swallowing dysfunction and response to treatment [61].

●Delayed puberty and fertility

•Male – Abnormalities in the pituitary testicular axis with a low plasma testosterone and high follicle and luteinizing hormone levels are common in male patients with cystinosis [62,63]. They may preclude full pubertal development. Male patients are usually azoospermic, but the presence of spermatogenesis in testicular biopsy may allow in vitro fertilization [62,64].

•Female – The mean age of puberty in affected females is 15 years [63], and successful pregnancies have been reported in women with cystinosis [65,66].

●Neurologic dysfunction – Children with cystinosis usually have normal cognitive function [67], but some patients may have mild neurocognitive abnormalities [68,69]. A subtle visuoperceptual defect and lower cognitive performances with impairment of visual memory and tactile recognition have been reported [70,71]. These findings may present as early as three to seven years of age, favoring the hypothesis of a direct role of the gene defect rather than cystine accumulation [72]. In addition, there is a report of an increased risk for Chiari I malformations in children with cystinosis [73].

More severe central nervous system involvement is a late complication that occurs after age 20 [74-77]. The main symptoms are difficulty in walking and swallowing [58,60], progressive loss of speech, memory loss, diminished intellectual function, and dementia. Pyramidal signs, cranial nerve defects, dysphagia, and dysarthria also may be seen. Stroke-like episodes with ischemic lesions have been reported. Benign intracranial hypertension may present with headaches and papilledema [78]. Findings detected by computed tomography (CT) or magnetic resonance imaging (MRI) include cerebral atrophy, dilated ventricles, basal ganglia calcifications, and patchy areas of demyelination.

●Bone disease – Bone disease occurs in some patients during adolescent and young adulthood presenting as scoliosis, vertebral fractures, decreased bone mass, bone deformations, and/or bone pain [79-83]. Although the pathogenesis is unknown, defective bone remodeling, resulting in diminished bone mass and the presence of microfractures, has been proposed as the underlying mechanism for the increased risk of bone fractures [84,85]. Other factors that contribute to bone disease include hypophosphatemic rickets due to phosphate wasting and hypophosphatemia, copper deficiency due to cysteamine toxicity, and chronic kidney disease [86].

●Cardiovascular calcification – Vascular calcifications of medium and large vessels including the coronary arteries were detected in 13 patients in a cohort of 41 individuals undergoing routine CT scans [87]. The rate of vascular calcification correlated directly with duration of life without cysteamine and correlated inversely with duration of life with cysteamine.

LATE-ONSET (JUVENILE) CYSTINOSIS — The clinical course is more indolent in older children who present with late-onset cystinosis. The first symptoms typically appear at age eight. The manifestations of Fanconi syndrome are less severe or absent, proteinuria may be in the nephrotic range, and end-stage kidney disease (ESKD) occurs after the age of 15 years [88,89].

The clinical presentation of late-onset cystinosis was reviewed in 14 patients from 9 unrelated families who were between 4 and 23 years of age at the time of diagnosis [39]. The following findings were noted:

●At presentation, 10 patients had symptoms of ocular discomfort and photophobia. In addition, all patients had cystine corneal deposits on slit-lamp examination and proteinuria; eight also had Fanconi syndrome.

●ESKD developed in four patients between 12 to 28 years of life. In addition, kidney transplantation was performed in four other patients including one patient who was diagnosed with cystinosis after transplantation. The reasons for kidney transplantation were not included.

●Genetic screening demonstrated CTNS variants in seven of the nine families, which were homozygotic in two families, compound heterozygotic in four families, and a single heterozygous variant in one family.

ADULT (BENIGN OR OCULAR) CYSTINOSIS — Adult (benign or ocular) cystinosis is characterized by the presence of cystine crystals in the eye and the bone marrow. Patients may suffer from photophobia, with the diagnosis being made by the observation of corneal crystal deposits by the ophthalmologist [34]. All systemic manifestations of the other forms of cystinosis are not present.

DIAGNOSIS — The diagnosis of cystinosis can be confirmed by one of the following three methods:

●Elevated cystine content of peripheral blood leukocyte or fibroblasts – In patients with nephropathic cystinosis, the free cystine content in leukocytes is approximately 10 to 50 times normal values [90,91]. The cystine binding protein assay has been replaced by the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Variability in the test results is due to different methods for white blood cell preparation, (ie, whether the test is performed on the whole white blood cell population or the isolated polymorphonuclear population), and the storage of the samples [92]. Cystine determination using immunomagnetic granulocyte purification followed by the LC-MS/MS improves the variability of mixed leukocyte analysis and eliminates the need for immediate sample preparation following blood draw [93]. The assay using the cystine binding protein is more sensitive and permits the detection of heterozygous carriers. The intraleukocyte cystine content is 5 to 15 nmol of half-cystine/mg protein in the infantile form, 3 to 6 nmol in the intermediate form, <1 nmol in heterozygous carriers, and <0.2 nmol in normal individuals [94]. A 2004 National Institutes of Health Cystinosis Conference suggested that an elevated leukocyte cystine level at any age (approximately 3 to 20 nmol of half-cystine/mg protein) provides a definitive diagnosis [91].

●Demonstration of cystine corneal crystals by slit lamp examination.

●Confirmation by genetic testing for pathologic variant(s) of CTNS – The diagnosis can be made by genetic testing that detect CTNS variants and can be performed in a number of laboratories throughout the world (laboratories for genetic testing of CTNS).

Prenatal diagnosis of an at-risk fetus can be established in the first trimester by molecular methods measuring 35S-labeled cystine incorporation into fibroblasts cultured from amniotic fluid or chorionic villi, directly or after culture [95]. The diagnosis can also be made by genetic testing if the variants on both alleles have been identified in an affected sibling [96].

TREATMENT — Therapy of cystinosis consists of amelioration of symptoms, the administration of cysteamine, and kidney transplantation for those who progress to end-stage kidney disease (ESKD) [97].

Symptomatic therapy — Symptomatic therapy is primarily needed for patients with infantile cystinosis.

●Fluid and electrolyte supplementation – The goal of fluid and electrolyte therapy for patients infantile cystinosis is to maintain adequate hydration by replacing fluid and electrolyte losses induced by the proximal tubular dysfunction. Fluid and electrolyte losses, and therefore the need for supplementation, diminish with age due to the progressive decline in glomerular filtration rate (GFR).

•Water intake has to be adjusted according to the urine output and should be increased during episodes of fever.

•Sodium and potassium bicarbonate supplements are given in order to maintain the plasma bicarbonate concentration between 21 and 24 mEq/L and to correct hyponatremia and hypokalemia. Some patients require as much as 10 to 15 mEq/kg of bicarbonate per day, since raising the plasma bicarbonate concentration above the reduced tubular reabsorptive capacity results in the rapid excretion of the exogenous bicarbonate in the urine. All these supplements need to be given regularly in order to replace ongoing losses.

●Indomethacin – Tubular losses of water, sodium, and potassium may be drastically reduced by indomethacin in a dose of 1 to 3 mg/kg per day [98]. Indomethacin therapy also improves appetite and growth. Although there is no consensus on the use of this drug in cystinotic patients, it appears to be relatively safe and well tolerated in young patients. It should be stopped in case of dehydration or if kidney function deteriorates. It should not be prescribed in association with angiotensin-converting enzyme (ACE) inhibitors [97].

●Nutritional, vitamin and mineral supplements

•Feeding problems may require tube or gastric button feeding, and in some cases continuous or intermittent total parenteral nutrition [99].

•Phosphate (1 to 3 g/day) supplementation is given to maintain the phosphate plasma level above 3.7 mg/dL (1.2 mmol/L) and prevent rickets.

•Vitamin D is given as 10 to 25 mcg/day of calcidiol (25-hydroxyvitamin D) or in a starting dose of 0.25 mcg/day of calcitriol (1,25 dihydroxyvitamin D). The dose of vitamin D should be adjusted according to the plasma calcium concentration.

●Other measures

•Thyroxine replacement is indicated in children with hypothyroidism.

•Growth hormone therapy is also safe and effective. Treatment should be started early in the course of the disease if adequate nutrition and cysteamine treatment do not prevent growth retardation [100,101].

•Hypersplenism with permanent leukopenia and/or thrombocytopenia may be an indication for splenectomy.

Cysteamine — Cysteamine therapy should be started as soon as the diagnosis of cystinosis is confirmed as it preserves kidney function, prevents hypothyroidism, and improves growth in affected children [102-104].

Mechanism of action — The administration of cysteamine directly treats the disease by reducing the intracellular cystine content. Cysteamine enters the cell and concentrates within the lysosomes, where it reacts with cystine to form both cysteine and a cysteine-cysteamine complex that are able to leave the lysosomes.

Efficacy — The efficacy of cysteamine in preserving kidney function was demonstrated by the following:

●In a study of 76 children (mean age 8.3 years) from the National Institute of Health (NIH), patients who were treated early (before two years of age) and adequately had a higher mean creatinine clearance than those who never received cysteamine (56 versus 8 mL/min per 1.73 m²) [102]. None of the 17 treated patients received kidney replacement therapy (KRT), whereas all of the 16 patients followed at the NIH who did not receive cysteamine received at a mean age of 8.3 years.

●In a study of 86 adults (mean age 26.7 years), cysteamine treatment beginning before 5 years of age decreased the incidence and delayed the onset of ESKD, and delayed the onset of hypothyroidism, diabetes, and neuromuscular disorders [105]. In this study, the mean age for onset of ESKD was 13.4 9.6, and 9.5 years for patients who received cysteamine therapy before 5 years of age (n = 40), after 5 years of age (n = 8) or never received cysteamine (n = 38) respectively. Cysteamine improved life expectancy with survival rates of 95, 57, 36 percent rate at the end of follow-up for patients who received cysteamine therapy before 5 years of age, after 5 years of age, or never received cysteamine, respectively.

However, cysteamine treatment does not correct proximal tubular dysfunction and has no effect on fluid and electrolyte losses, even when started after birth in children who have been diagnosed antenatally. However, children treated early and adequately (as assessed by depletion of cystine from leukocytes), show improved growth and maintenance of the GFR and are less likely to develop hypothyroidism [103,106]. Poorly compliant patients and those treated at an older age do not have as great a benefit [105].

Ophthalmic, but not systemic, cysteamine is effective in preventing corneal crystal deposition and in reducing photophobia [107]. (See 'Cysteamine topical eye treatment' below.)

Oral formulation and dosing — The most commonly used formulation is the immediate-release preparation of cysteamine bitartrate. The dose should be progressively increased from 10 to 50 mg/kg per day (maximum dose of 1.95 gm/m² per day), given in divided doses every six hours. Levels of cystine are measured in white blood cells once the maintenance dose is reached, then monthly for three months, quarterly for one year, and then twice a year. The optimal target level is less than 1 nmol half-cystine/mg protein. Blood sampling should be obtained six hours after taking a dose of cysteamine.

The enteric-release formulation (delayed-release) given every 12 hours is as effective as the immediate-release form, which needs to be given more frequently to maintain white blood cystine levels within a satisfactory range [108-110]. In 2020, the US Food and Drug Administration (FDA) approved the use of delayed-release oral cysteamine for use in patients with cystinosis including children.

●Dosing conversion from immediate to delayed release formulation ‒ In converting from the immediate to the enteric-release formulation, the manufacturer suggests that the starting total daily dose of the enteric-release formulation should be equal to the previous daily dosage of the immediate-release cysteamine.

●Initial dosing in naïve patients ‒ The enteric-release formulation may also be used as initial therapy. Similar to the immediate-release preparation, initiation of enteric-release cysteamine is started at one-sixth to one-fourth of the maintenance dose (1.3 g/m² per day). Dosage is gradually increased by 10 percent increments to the recommended maintenance dose over two-week intervals for patients one to less than six years of age and for older children, over four to six weeks intervals while monitoring white blood cell (WBC) cystine levels. If a patient achieves the therapeutic WBC level, dosage escalation is stopped. The maximum dose for patients is 1.95 gm/m² per day.

Adverse effects — Side effects of the orally administered drug include nausea and vomiting, which can be managed with omeprazole [111]. Less commonly, allergic rashes, seizures, and neutropenia are seen. In addition, cysteamine is responsible for unpleasant breath and sweat odor, so long-term compliance is difficult to maintain, especially in adolescents [112,113].

Other side effects, such as bruise-like skin lesions at the elbow and knee due to vascular proliferation, neurologic symptoms, and muscle pain have been reported when the dosing exceeds the maximum daily dose of 1.95 gm/m² [114]. In most cases, these side effects resolved with a reduction in cysteamine dosing. In patients with drug toxicity, a dose reduction of 25 percent based on body surface area is suggested with careful monitoring of intraleukocyte cystine content to ensure that underdosing does not occur.

Patients with severe, persistent, and/or worsening abdominal symptoms should be evaluated for fibrosing colonopathy, a serious intestinal fibrotic process associated with strictures and, in some cases, ascites. This may be due to an association between fibrosing colonopathy and methacrylic acid-ethyl acrylate copolymer, which is an inactive ingredient in the delayed release formulation of cysteamine [115].

It has been suggested that copper deficiency plays a role in cysteamine toxicity, particularly in patients with Fanconi syndrome who have increased urinary copper excretion [116]. The proposed mechanism is that copper deficiency results in decreased activity of lysyl oxidase, an enzyme required for the production of collagen cross-linking aldehydes needed to form the cysteine-cysteamine complex, which is able to exit the lysosome. However, further research is needed to determine whether copper supplementation can reduce the risk of adverse effects.

Pregnancy — Based on animal data, cysteamine treatment should be discontinued in women during pregnancy [117].

Cysteamine topical eye treatment — Ocularly administered cysteamine should be prescribed to prevent corneal deposits, because the oral formulation does not reach the cornea due to absent corneal vascularization [118]. Several reports indicate that topical cysteamine can dissolve cystine corneal deposits and improve photophobia [107,118]. However, compliance is challenging as the eye drop solution has to be given at least four times a day while awake in order for the drops to be effective [119,120]. In addition, problems with storage and frequent refills makes adherence difficult, as the eye drop solution has to be kept in the cold until opened and be used within one week after opening.

A retrospective case series of 32 patients reported varying success of topical cysteamine eye drops 0.55 percent over the mean study period of 4.1 years (range 2 to 8 years) [121]. In this cohort, there was no change in corneal deposits in 21 patients, and 11 developed more severe corneal deposits while on therapy. Of the 18 patients with photophobia, seven reported improvement of symptoms, six with no change in symptoms, and the remaining five had worsening symptoms. These results differ from previous observations that were conducted in a research setting and could be explained by poor adherence for effective administration, low concentration of cysteamine, poor absorption (perhaps due to genetic variation), and severity of disease.

A gel formulation of topical cysteamine has been developed, which has shown superior efficacy while requiring a less frequent schedule of administration and may prove to be more effective in improving the outcome of patients with corneal deposits [122-124].

Kidney transplantation — Kidney transplantation is successful in patients with ESKD with excellent long-term kidney outcome [91,125]. Cystine-induced tubular dysfunction does not recur on the graft, although cystine does accumulate in the interstitial cells. After kidney transplantation, cysteamine treatment should be given as soon as possible [126].

However, there is considerable long-term morbidity from extrarenal cystinosis following kidney transplantation [87,125,127,128]. In one study of 36 patients, for example, 31 were taking thyroid hormone replacement, 21 had moderate to severe swallowing abnormalities, 8 had cerebral calcifications, and 5 were blind [127]. Few patients over the age of 20 had no serious complications, and those over the age of 30 were usually doing poorly, although many were still working. Lack of prolonged compliance with cysteamine therapy may have been a major cause of these problems, as only 11 patients received adequate treatment. It is estimated that depletion of excess cystine from muscle requires 4 to 11 years of therapy.

Potential future interventions

●Hematopoietic stem cell transplantation –Based on previous animal data, an allogenic hematopoietic stem cell transplantation was performed in a 16-year-old boy with infantile cystinosis and serious side effects of cysteamine therapy [129]. Although the patient died from infectious complications three years later, there was expression of the wild-type allele of CNTS in the recipient epithelial cells, reduction of cystine crystal accumulation, and resolution of photophobia.

●Luteolin – Luteolin, which ameliorates lysosomal abnormalities of cystinotic cells and has a good safety profile, has potential as a treatment for nephropathic cystinosis [130].

OUTCOME — Long-term sustained cysteamine therapy into adulthood appears to improve patient outcome. Despite this treatment, patients with cystinosis have significant morbidity and mortality.

The outcome of patients and effects of oral cysteamine therapy were evaluated in a large case series of 100 patients who were enrolled in the National Institutes of Health's (NIH) cysteamine trial from 1985 to 2006 [131]. The following findings were noted:

●Kidney transplantation was performed in 92 patients at a mean age of 12.3 years.

●Thirty-three patients died at a mean age of 28.5 years (range 18 to 43 years).

●Patients had significant nonrenal abnormalities including hypothyroidism (75 percent), pulmonary insufficiency (69 percent), swallowing abnormalities (60 percent), myopathy (50 percent), hypercholesterolemia (33 percent), retinopathy (32 percent), vascular (31 percent) and cerebral calcifications (22 percent), and diabetes mellitus (24 percent). Hypergonadotropic hypogonadism was present in 74 percent of males.

●Patients who received sustained long-term oral cysteamine therapy (greater than eight years) compared with those receiving a shorter course had better growth, kidney transplantation at a later age, lower cholesterol levels, fewer complications, and a lower mortality rate.

Delay in treatment negatively impacts cognitive function. In a study of 46 children (mean age 7.3 years, range 3 to 18 years of age) with cystinosis, children who were treated after two years of age performed lower on verbal, performance, and visual-spatial skills, and full-scale intelligence quotient (IQ) measures than patients who had been treated before two years of age and age-matched controls [68].

In the previously mentioned study evaluating the effects of cysteamine in 86 adult patients (mean age 26.7 years), initiating cysteamine treatment before five years of age decreased the incidence or delayed the onset of ESKD, and delayed the onset of hypothyroidism, diabetes, and neuromuscular disorders, and improved life expectancy [105].

SUMMARY AND RECOMMENDATIONS

●Introduction and definitions – Cystinosis is a metabolic disease characterized by an accumulation of cystine in different organs and tissues leading to potentially severe organ dysfunction including end-stage kidney disease (ESKD).

Cystinosis is classified into three forms based upon the age of presentation and severity of symptoms: the infantile (nephropathic) form, the late-onset (juvenile) form, and the adult (benign) form. (See 'Definition' above.)

●Pathogenesis and genetics – Cystinosis is an autosomal recessive trait that is due to variants of the CTNS gene, which encodes cystinosin. Cystinosin is a novel transporter that is responsible for exporting cystine from lysosomes. (See 'Genetics' above.)

●Infantile cystinosis – Infantile cystinosis is the most common and severe phenotype. Patients present between three and six months of age with signs and symptoms due to renal tubular dysfunction. These include polyuria, polydipsia, poor weight gain, vomiting, weakness, unexplained fever, and acute episodes of hypovolemia. These children have a progressive decline in glomerular filtration rate (GFR), resulting in ESKD by 10 years of age if untreated.

Nonrenal findings include ocular abnormalities, hepatomegaly, hypothyroidism, muscle weakness, and growth retardation. Although cognitive function is normal in children, complications of the central nervous system occur after 20 years of age. In affected males, delayed puberty is common. (See 'Infantile cystinosis' above.)

●Late-onset (juvenile) cystinosis – Late-onset (juvenile) cystinosis generally presents around eight years of age with manifestations due to renal tubular dysfunction. These patients also have a progressive decline in GFR, resulting in ESKD by 15 years of age. (See 'Late-onset (juvenile) cystinosis' above.)

●Adult cystinosis – Adult cystinosis is the most benign form. Patients are generally asymptomatic except for photophobia or ocular discomfort due to crystal deposition in their cornea. (See 'Adult (benign or ocular) cystinosis' above.)

●Diagnosis – The diagnosis of cystinosis is confirmed by one of three methods: elevated intraleukocyte cystine content, the demonstration of cystine corneal crystals by slit lamp examination, or the detection of CTNS gene variant. (See 'Diagnosis' above.)

●Management

•Symptomatic treatment – Symptomatic treatment includes fluid and electrolyte phosphorus and vitamin D repletion and maintenance to account for renal proximal tubular loss. (See 'Symptomatic therapy' above.)

•Cysteamine – We recommend treating all patients with cysteamine as soon as the diagnosis of cystinosis is confirmed (Grade 1B). Early treatment with cysteamine decreases and delays the risk of ESKD, hypothyroidism and diabetes; and improves growth and survival. Ocular administration of cysteamine reduces ocular discomfort and photophobia. However, cysteamine treatment does not correct proximal tubular dysfunction and has no effect on fluid and electrolyte losses. Adverse effects may also affect patient compliance. (See 'Cysteamine' above and 'Outcome' above.)

•Kidney transplantation – In patients who develop ESKD, kidney transplantation is the preferred therapy, as outcome is excellent. However, kidney transplantation does not prevent long-term morbidity from extrarenal cystinosis. (See 'Kidney transplantation' above.)