Part 21: Membrane Transport Disorders Chapter 199: Cystinosis: A Disorder of Lysosomal Membrane Transport

Chapter 199: Cystinosis: A Disorder of Lysosomal Membrane Transport
PART 21: MEMBRANE TRANSPORT DISORDERS

William A. Gahl, Jess G. Thoene, Jerry A. Schneider
Abstract
1. Cystinosis is a rare, autosomal recessively inherited lysosomal storage disorder due to defective
carrier-mediated transport of the amino acid cystine across the lysosomal membrane. The major
clinical manifestation of cystinosis is renal failure at approximately 9 to 10 years of age. The
cystinosis gene has been isolated, and several different mutations identified.
2. In cystinosis, free, nonprotein cystine accumulates to 10 to 1000 times normal levels and forms
crystals within the lysosomes of most tissues, which are damaged at different rates. The diagnosis is
made by demonstrating an elevated cystine content in polymorphonuclear leukocytes or cultured
fibroblasts or by slit-lamp examination showing corneal crystals which are generally present in
patients over 1 year of age. Cystinosis can be diagnosed in utero by cystine measurements in
amniocytes or chorionic villi, or at birth by cystine measurements of the placenta.
3. Children with cystinosis are normal at birth but develop signs of the renal tubular Fanconi syndrome,
usually between 6 and 12 months of age. These include dehydration, acidosis, vomiting, electrolyte
imbalances, hypophosphatemic rickets, and failure to grow. Weight is proportional to height. Head
circumference and intelligence are spared. Other manifestations of cystinosis include photophobia,
hypothyroidism, and decreased ability to sweat. Renal glomerular damage progresses inexorably,
requiring dialysis or transplantation at 6 to 12 years of age.
4. Cystine storage does not occur in the donor kidney, but continued accumulation in the host tissue can
result in retinal blindness, corneal erosions, diabetes mellitus, a distal myopathy, swallowing
difficulties, decreased pulmonary function, pancreatic insufficiency, primary hypogonadism in males,
and neurologic deterioration in a significant number of post-renal transplant patients 13 to 40 years
old.
5. The cystinosis gene, CTNS, is located on chromosome 17p13, has 12 exons spanning 23 kb of
genomic DNA, and codes for a 367-amino-acid protein called cystinosin, with 7 transmembrane
domains and 8 potential glycosylation sites. Approximately 40 percent of cystinosis patients from
northern Europe are homozygous for a 57-kb deletion that disrupts CTNS. Twelve percent of the 216
alleles of an American-based cystinosis population contain a 753G → A (W138X) mutation.
Twenty-nine other mutations have been identified to date.
6. Therapy for cystinosis includes replacement of renal losses due to the Fanconi syndrome; provision
of thyroxine, insulin, pancreatic enzymes, and testosterone for deficient patients; and symptomatic
care of ophthalmic complaints. Chronic cystine-depleting therapy with the aminothiol cysteamine
significantly lowers leukocyte and parenchymal cystine levels, improves growth, and obviates the
need for thyroid hormone replacement. More importantly, oral cysteamine therapy preserves renal
function and, if initiated in the first 2 years of life, can allow for a net increase in the glomerular
filtration rate. Side effects include nausea and vomiting. Cysteamine eyedrops can dissolve corneal
crystals in young children and remove the haziness from the corneas of older patients.
7. The clinical course and severity of cystine accumulation in cystinosis vary in different kindreds, from
ocular cystinosis in adults with corneal crystals but no renal disease to intermediate cystinosis in
adolescents with late-onset renal deterioration, and finally to classic nephropathic cystinosis in
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infants. Heterozygotes for all types of cystinosis are clinically normal.
Cystinosis is a lysosomal storage disorder resulting from defective transport of cystine (Fig. 199-1) across
the lysosomal membrane. The term cystinosis can refer to one of several variants of the disease but,
unless specified, here denotes nephropathic cystinosis, which results in renal failure at approximately 9 to
10 years of age. Cystinosis is now recognized as a systemic disorder, with variable onset of symptoms for
the different tissues affected. Cystinosis represents a prototype for metabolic disorders due to defective
integral lysosomal membrane transport proteins. Its gene, CTNS, resides on chromosome 17p and has
been recently cloned and sequenced.
Structures of the disulfide amino acid cystine, which is stored in cystinosis, and the aminothiol cysteamine,
which depletes cells of cystine.
HISTORICAL ASPECTS
The current understanding of cystinosis as an inherited, multisystemic disease resulting from failure of
lysosomal cystine transport follows from more than eight decades of both clinical and laboratory research.
Over this time, a number of basic issues were addressed: (a) What is the clinical phenotype of the
disease? (b) Is cystinosis different from renal Fanconi syndrome and cystinuria? (c) Where in the cell is
the cystine stored? (d) Do the crystals form in situ or are they phagocytosed from preformed crystals in
the extracellular fluid? (e) What is the source of the stored cystine? (f) Why does the cystine accumulate?
(g) What causes the renal failure in cystinosis? (h) How can the disease be treated? (i) What is the nature
of the molecular pathology accounting for this fatal disease? The answers to all these questions are now
known with varying degrees of certitude except what causes the renal failure. The toxic nature of stored
lysosomal cystine is still not understood, although plausible hypotheses involving inactivation of critical
thiol moieties in intracellular enzymes have been proposed.
Cystinosis was first recognized as a clinical entity by Abderhalden in a 1903 manuscript entitled “Familiare
Cystindiathese.” 1 He described several children in whom abnormal accumulations of cystine were found.
One child demonstrated failure to thrive at 21.5 months of age. In this child’s internal organs, white
punctate lesions were demonstrated to consist of the amino acid cystine upon classical chemical analysis
via formation of the naphthol derivatives. Unfortunately, Abderhalden also reported several children with
cystine stones and with excess cystine in the urine, leading to a persistent confusion between cystinosis
and cystinuria. 1
Following Abderhalden’s seminal work, the description of this syndrome was enlarged by a number of
European authors. Lignac’s 1924 report of cystine deposits in each of three infants with rickets, dwarfism,
renal disease, and wasting provided some delineation of the clinical aspects of cystinosis. 2 In 1931,
Fanconi described nondiabetic glycosuria, 3 and in 1935, de Toni described vitamin D-resistant rickets
with spontaneous fractures in a dwarfed child who also had hypophosphatemia, acidosis, albuminuria,
and glucosuria. 4 Report of a similar child by Debré et al. in 1934 led to the condition being termed de
Toni-Debré-Fanconi syndrome. 5 Nephrotic glucosuria with hypophosphatemic rickets was reported as a
distinct clinical entity in 1936, emphasizing the early onset, severe rickets, thermolability, and abnormal
tubular vacuolization of the disorder; parental consanguinity suggested autosomal recessive inheritance. 6
In 1937, Beumer and Wepler reemphasized the presence of massive amounts of crystals in the internal
organs in children with “renal diabetes,” clearly connecting cystine to this clinical entity. 7 Bickel and
colleagues provided further evidence of the association of cystinosis with the Fanconi syndrome and with
progressive glomerular damage. 8, 9
Experimental work in both rabbits and dogs had previously demonstrated severe renal toxicity when
cystine was administered orally or intravenously. The animals developed renal lesions characterized by
massive proteinuria, swollen renal tubular cells, and renal casts. All other amino acids spared the kidneys
except tyrosine, another relatively insoluble amino acid. 10 The aminoaciduria in cystinosis was
extensively studied by Dent who, in 1947, also quantified the extent of polyuria, glucosuria, phosphaturia,
and proteinuria. 11 Dent also noted that the generalized aminoaciduria in cystinosis was not due to
“overflow” of plasma amino acids and that no obvious error of sulfur amino acid metabolism was present
in these patients. The clear distinction between cystinosis and cystinuria was first provided in 1949, 12
when the familial nature of both diseases was recognized, and the rarity of cystine stones in patients with
cystinosis was appreciated. Further details on the early investigations of this disorder are available
elsewhere. 13–15
The precise location of the cystine crystals was difficult to ascertain, but Barr 16 and Bickel concluded
correctly that they were primarily intracellular and within reticuloendothelial cells. Clay and colleagues
demonstrated in histologic studies of cystinotic kidney that many nephrons were hypotrophic, particularly
in the proximal convoluted tubules, with narrowing in the first part of the tubule forming a “swan-neck”
lesion. 17 Darmady and others showed that these lesions are not specific for cystinosis, but are seen in
other renal conditions as well. 9, 18 In 1962, electron microscopy of renal biopsy specimens demonstrated
hexagonal crystals between tubules in the kidney, and the pathognomonic “swan-neck” deformity of the
proximal tubule was confirmed on light microscopy. 19 Vacuolation and swelling of the endoplasmic
reticulum were noted, and cytoplasmic bodies were found in the apical and central portions of the cell,
frequently with coarse granules in the proximal convoluted tubule. It was concluded that crystallization of
cystine between cells, secondary to some unknown primary metabolic or enzymatic defect, led to the
renal pathology.
The modern era of clinical investigation into cystinosis began in 1967, when the intracellular location of the
stored cystine was identified as the lysosome. This was demonstrated by differential centrifugation of
leukocyte 20 and fibroblast 21 subcellular fractions; by electron microscopy in lymph node cells, 22
histiocytes, 23 and rectal mucosal cells; 24 by ferritin labeling; 25 by sucrose density gradients; 26 and by
exposure of cystinotic fibroblasts to L-cysteine-D-penicillamine disulfide to selectively induce vacuolation. 27
Next, the metabolism and plasma membrane transport of cysteine and cystine were investigated in
cystinotic fibroblasts and leukocytes, with no consistent demonstration of a defect compared with
normal. 28 In particular, enzymes involved in cyst(e)ine and glutathione redox reactions were not impaired
in cystinotic tissues and cells. 28, 29
These findings, detailed previously, 28 set the stage for pursuit of the hypothesis that transport of small
molecules across the lysosomal membrane was carrier-mediated. 30 To directly investigate this possibility
for cystine, normal polymorphonuclear leukocytes were loaded to very high cystine concentrations by
exposure to cystine dimethylester, which, like other amino acid methylesters, 31, 32 was specifically
hydrolyzed within lysosomes to methanol and free cystine. This ingenious technique, suggested by Dr.
Frank Tietze and exploited in Dr. Joseph Schulman’s laboratory in the early 1980s, allowed normal and
cystinotic leukocytes to be equivalently loaded with cystine. Subsequent whole cell egress studies, using
either 35 S-cystine or nonradioactive cystine, revealed rapid losses of cystine from normal cells (t ½
approximately 45 min) and slow losses from cystinotic cells (t ½ approaching infinity). 33 At the same time,
investigators in Dr. Jerry Schneider’s laboratory were loading cultured fibroblasts with cystine by exposing
them to 30 mM cysteine-glutathione mixed disulfide for 24 h. With low, but roughly equal, initial loadings,
the normal cells lost half their cystine in 20 min, while the cystinotic cells lost none in 90 min. 34
Experiments using isolated leukocyte lysosomes verified the whole cell results, with 13 normal granular
fractions having a mean t ½ for 35 S-cystine of 26.1 ± 1.4 SEM min and 12 cystinotic granular fractions
having a mean t ½ of 80.8 ± 0.7 min. 35 Nonradioactive experiments gave similar results, regardless of the
initial level of cystine loading. 35 EBV-transformed lymphoblasts, loaded using cystine dimethylester,
showed a rate of cystine efflux that was two to three times greater in normal compared with cystinotic
granular fractions. 36 Comparable experiments in fibroblasts using either [ 35 S] cystine 37, 38 or
nonradioactive cystine 38 also revealed short half-times for cystine egress from normal lysosomes and
very long half-times using cystinotic lysosomes.
A major advance was the expression of egress rates as initial velocities, 39 which increased linearly with
loading of normal lysosomes and then leveled off (Fig. 199-2), indicating saturation kinetics, a hallmark of
carrier-mediated transport. Cystinotic granular fractions displayed negligible velocities of cystine egress,
regardless of the level of cystine loading. Cystinosis heterozygotes exhibited a V max half that of
normals. 39
Initial velocity of cystine transport as a function of lysosomal cystine loading using human leukocytes.
Normal egress velocity increased with loading and then plateaued, indicating saturation kinetics.
Heterozygotes for cystinosis followed a similar pattern but reached only half the normal maximal velocity.
Cystinosis patients displayed negligible egress velocity regardless of the level of loading. Values were
normalized to the activity of ...
Finally, the carrier-mediated nature of lysosomal cystine transport was proven definitively by the
demonstration of cystine countertransport or trans-stimulation. In countertransport, tracer amounts of a
radiolabeled substance will cross a membrane at an increased rate if there is a substantial concentration
of the nonradioactive substance on the opposite side of the membrane. 40 Thus, normal leukocyte
lysosomes loaded with nonradioactive cystine took up [ 3 H]cystine (present in tracer concentrations) more
rapidly than lysosomes not loaded with cystine, 41 proving that a carrier for cystine was present in the
lysosomal membrane. Cystinotic granular fractions took up virtually no [ 3 H]cystine, regardless of the level
of loading. 41 Obligate heterozygotes for cystinosis exhibited half the normal [ 3 H]cystine
countertransport. 42
Following this demonstration, other lysosomal transport systems were rapidly described. At the present
writing, more than 20 are known, including systems that recognize all categories of amino acids, inorganic
anions and cations, carbohydrates, nucleosides, and cobalamin. 43 Thus, the solution to the cell biology
question “Why does lysosomal cystine accumulate?” led to a greatly enhanced understanding of a
previously unknown area of cell biology, that of mediated lysosomal transport. The signal role cystinosis
has played in allowing delineation of this previously unknown area of cell biology deserves emphasis in
the current debate over “translational” research.
In 1995, the cystinosis gene was mapped to chromosome 17p by a consortium of investigators 44 using
polymorphic microsatellite repeat markers. In 1998, the cystinosis gene was isolated and a variety of
causal mutations identified 45 (see “Genetics” below).
CYSTINE
Chemical Properties
Cystine, the disulfide of the amino acid cysteine, has a molecular weight of 240.3. Cystine and cysteine
participate in a reversible oxidation-reduction reaction whose redox potential is −0.22 eV 46 or even more
negative. In the presence of oxygen, cysteine is rapidly oxidized to cystine. Cystine’s two carboxyl groups
and two amine residues have pK a s of <1, 1.7, 7.48, and 9.02, respectively; 47 its net charge at
physiological pH is zero, and its pI is 4.60. 47 The disulfide’s solubility in water at 25°C approximates
0.5 mM at pH 7.0, 48 but heating or the use of small volumes of dilute (0.01 N) acid or alkali facilitates
crystal dissolution. The poor solubility of cystine in aqueous solution explains the formation of urinary
crystals and renal calculi in cystinuria, a defect of tubular reabsorption of cystine and dibasic amino acids
(see Chap. 191). Human plasma at 37°C and pH 7.3 can dissolve approximately 1.67 mM cystine. 13
Cystine’s insolubility in alcohol provides the basis for the preservation of cystine crystals in cystinotic
tissue by alcohol fixation; the use of aqueous solutions can dissolve the intracellular crystals. The dibasic,
diacidic nature of cystine distinguishes it from glutamate and explains the difference between plasma and
lysosomal transport of cystine. 43 At neutral pH, both glutamate and cystine are tripolar acidic, and both
are recognized by a single transport system in the plasma membrane of fibroblasts. 49 However, at the
intralysosomal pH of 5, cystine’s second amine is protonated and the compound is now tetrapolar neutral,
whereas glutamate, lacking the second amino group, remains tripolar acidic. Hence, the lysosomal
membrane transport system distinguishes between the two amino acids, recognizing only cystine. 43
Metabolism
Cystine forms largely by the direct oxidation of two cysteine molecules. Cysteine is both a precursor in
protein synthesis and a product of protein hydrolysis. It is also synthesized de novo, deriving its sulfur
atom from the essential amino acid, methionine. The transsulfuration of methionine yields homocysteine,
which combines with serine to form cystathionine, the proximate precursor of cysteine through the
enzymatic activity of cystathionase (see Chap. 88). In conditions in which cystathionine β-synthase or
cystathionase is deficient, 50 for example, in homocystinuria or cystathioninuria, or in normal human
fetuses and neonates, 51 cysteine becomes an essential amino acid. Cysteine (or cystine) is also required
for the growth of normal human fibroblasts, 52 but not normal human lymphoid cells, 53 in culture. In vivo,
cysteine is oxidized to inorganic sulfate by one of several pathways 15 for excretion in the urine. It can also
be incorporated into free thiols such as glutathione (GSH, γ-glutamylcysteinylglycine), through the
γ-glutamyl cycle.
Because of the many cystine-reducing systems present in the cytosol, most cellular cyst(e)ine exists in the
free thiol form. It is maintained as cysteine by GSH-disulfide transhydrogenases 54 acting in concert with
high cellular concentrations of reduced glutathione (up to 10 mM 55 ). Cystine and GSH participate in a
disulfide interchange reaction 56 to form cysteine and cysteine-GSH mixed disulfide; a second reaction
between reduced GSH and the mixed disulfide produces cysteine and oxidized glutathione. The same
type of disulfide interchange reaction provides the basis for the reduction of cystine by cysteamine (see
“Mechanism of Cystine Depletion by Cysteamine” below). These disulfide interchange reactions and their
products occur within the cytosol, and isolated reports of lysosomal cystine-reducing systems 57 have not
been supported in subsequent investigations. 29 Disulfide bonds have been exploited in intermediary
metabolism to assist in the maintenance of the tertiary structure of a variety of proteins. Fahey noted that
extracellular proteins have a high cystine content (4.1 percent) whereas intracellular proteins have a low
concentration (1.6 percent). He suggested that disulfide proteins evolved after the accumulation of oxygen
in the atmosphere. 58, 59
Methods of Assay
Cystine can be reduced to cysteine and measured qualitatively by the cyanide-nitroprusside reaction. 60
Semiquantitative assays employ paper 61 or thin-layer 62 chromatography. The routine quantitation of
cystine in plasma or urine involves separation from other amino acids by ion-exchange chromatography
and identification by ninhydrin staining. 63 The procedure measures total cystine plus cysteine; it cannot
differentiate the two. This explains the conventional use of “half-cystine” to express amounts of the
disulfide. Most current research employs the Escherichia coli cystine-binding protein assay 64 to
specifically measure picomole quantities of cystine in protein-free extracts. This assay also allows
physicians to diagnose cystinosis and follow cystine depletion by cysteamine. The assay involves
competition by unknown quantities of nonradioactive cystine for [ 14 C]cystine bound to the protein, with
trapping of protein-bound radioactivity on nitrocellulose filters. The less radioactivity that is trapped, the
greater the competing nonradioactive cystine.
Cystine Storage in Cystinosis

Plasma cystine concentrations are normal in cystinosis. 13 Intestinal absorption of cystine is normal, and
urinary cystine levels are no more elevated than those of other amino acids, differentiating cystinosis from
cystinuria (see Chap. 191). Rather, cystine storage in cystinosis is intracellular (Fig. 199-3), with crystal
formation in the kidney; 65 liver; 66 lung; 67 pancreas; 68 intestine; 69, 70 appendix; 71 spleen; 72 conjunctiva
and cornea; 73 retina; 74 lymph node; 22 polymorphonuclear leukocyte and monocyte; 75 bone marrow; 76
thyroid; 77 thymus; 78 muscle; 79 placenta; 80 choroid plexus; 81, 82 meninges; 79 and gingival tissue. 83 Pure
cystine crystals can be rectangular, in which case they are birefringent 13 or hexagonal. Cystine
hydrochloride crystallizes as prismatic needles; 84 this describes the corneal crystals in cystinosis. Various
peripheral leukocyte populations 85 and all cells in culture remain devoid of crystals but accumulate 5 to
500 times normal amounts of cystine (Table 199-1). Cystine accumulation and crystal formation occur
according to a tissue-specific chronology, with considerable variation among individual patients. Corneal
crystals may not be present until 1 year of age, yet crystals have been identified in the Kupffer cells of a
22-week fetus. 86 The brain white and gray matter may be entirely spared of cystine accumulation in a
young cystinosis patient, 87 yet show several-fold increased cystine levels in a 25-year-old woman with
cystinosis. 88 Both muscle and liver cystine levels increase with age in cystinosis patients who have not
received cystine-depleting therapy. 89, 90 The reasons for variable rates of cystine accumulation among
different tissues are unknown, but may be related to different rates of protein degradation and cell
turnover.
Table 199-1: Cystine Content of Cystinotic Tissue and Cells
Cystinotic Normal
x¯ ±
N x¯ ± SD Range N Range Reference
SD
nmol
mol half-cystine/mg
Tissues half-cystine/mg
wet weight
wet weight
Kidney 1 25.6 – 156
94.8 ±
4 24.6–29.5 1 0.25 – 87
79.7
51.4 ±
5 16.7–101.7 ? – <0.29 257
32.6
64.7 ±
3 39.2–80.0 – 338
22.2
1 – 19.8, 21.0 – 339
1 0.28 * – – 340
117.9 ±
Conjunctiva 7 5.2–314.0 13 – <0.38 203
115.3
0.023
0.77 ±
Muscle 10 0.05–1.94 10 ± – 89
0.53
0.003
0.31 ±
3 0.06–0.95 1 0.003 – 211
0.23
2.27 ±
12 0.23–12.30 1 0.004 79, 90
3.35
Brain 2 – 0.02–0.08 1 0.17 – 87
1 – 0.05–0.20 – 339
1 – 0.80–4.0 – 79
Lung 1 44.5 – 156
Pancreas 1 35.8 156
1 40.2 79
73.0 ±
Liver 3 45.8–112.5 2 – 0.58, 0.92 338
35.0
1 69.1 – 156
1 – 34.5, 42.4 – 339
0.04
4 2.0–360.0 4 ± 0.02–0.10 90
0.04
Gallbladder 1 2.1 – – 156
Spleen 1 132.7 79
1 119.0 90
nmol
nmol half-cystine/mg
Cells half-cystine/mg
protein
protein
0.08
Polymorphonuclear 6.4 ± 20, 21,
9 4.0–13.2 9 ± <0.2
leukocytes 2.8 326
0.06
3 – 6.9–10.0 2 – <0.1 311
0.14
8.9 ±
29 2.6–23.1 29 ± 0.04–0.28 42, 156
4.7
0.06
0.07
8.4 ±
Cultured fibroblasts 6 6.6–10.6 9 ± <0.2 21, 326
1.3
0.05
6 – 6.7–14.3 3 – <0.1 311
Cultured leukocytes 3 – 0.31–3.10 3 – <0.03 341
Epstein-Barr 0.10
0.46 ±
virus-transformed 3 – 3 ± – 36
0.10
lymphoblasts 0.02
Cultured 29.8 ±
1† 16.7–41.2 1 0.31 – 211
myoblasts/myotubes 10.8
23.2 ±
Cultured cornea 1 11.0–38.7 1 0.27 – 295
14.1
0.06
8.0 ±
Cultured renal cells 1 – 1‡ ± – 342
0.6
0.02
Cultured renal
1 3.5 – 1 0.06 – 343
tubular cells
* The patient was receiving long-term cysteamine therapy at the time the biopsy was taken.
Cystine crystals. A, Light microscopy showing conjunctival crystals under cross-polarizing light.
B, Electron micrograph of hexagonal cystine crystals within lysosomes of a Kupffer cell. ×14,500.
C, Scanning electron micrograph showing crystals protruding from the surface of a Kupffer cell.
×1800. (B and C courtesy of K.G. Ishak, M.D., Ph.D., Armed Forces Institute of Pathology,
Washington, DC.)
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† When a single individual’s cells were studied, the mean ± SD for at least three separate cultures
is given.
‡ Madin-Darby canine kidney epithelial cells; human renal cells in culture were not available.
Circulating leukocytes from cystinosis patients exhibit normal morphology and normal cysteine
concentrations. 20 Cystinotic polymorphonuclear leukocytes, as well as cultured fibroblasts, myoblasts,
corneal cells, and renal epithelial and tubular cells, contain fiftyfold to one hundredfold normal amounts of
cystine (Table 199-1). Leukocyte cystine values do not change significantly with age in cystinosis
patients. 91
Lysosomal Cystine Transport

Early studies using polymorphonuclear leukocytes delineated several characteristics of lysosomal cystine
transport. For example, because N-ethylmaleimide did not affect the egress of cystine from normal
lysosomes, 39 it was clear that cystine was not being reduced to cysteine and reoxidized to cystine during
the transport process; cystine itself was the transported ligand. Moreover, the fact that cystinotic granular
fractions cleared tryptophan and methionine in a normal fashion 35 meant that the lysosomal cystine
carrier exhibited some specificity.
That specificity was investigated using the powerful technique of countertransport. In particular, normal,
cystine-loaded granular fractions did not countertransport other amino acids such as 35 S-homocystine
except, to a certain extent, 35 S-cystathionine. 41 Extralysosomal nonradioactive L-cystine, but not
D-cystine, competed with [ 3 H]cystine for uptake into cystine-loaded normal granular fractions, 41
establishing the stereo-specificity of the carrier for the L isomer. The carrier presumably also recognized
certain sulfur compounds that resembled cystine, such as cystathionine and cystamine, because they
competed with cystine for countertransport. 41 Because the dibasic amino acid, arginine, did not compete
with cystine, the carrier was presumed to be different from the plasma membrane carrier for dibasic amino
acids in renal tubular and intestinal epithelial cells (see Chap. 191). The lysosomal cystine carrier did not
recognize glutamate, 41 indicating that it was genetically distinct from the plasma membrane cystine
carrier of fibroblasts that transports both cystine and glutamate. 49 Several other amino acids—that is,
methionine, alanine, tryptophan, tyrosine, and homocystine, as well as β-carboxyethyl-L-thiocysteine and
other cystine analogues—also did not compete with cystine for transport. 41 The cystine carrier appeared
specific for compounds of chain length 6 (not 8) sulfur or methylene units having an amine (but not
necessarily a carboxyl) group at each end. Similar ligand preferences have been demonstrated for
lysosome cystine transport in mouse L-929 cells, where it was also shown that selenium could substitute
for sulfur, and the carrier’s recognition site for cystine was dominated by hydrophobic interactions. 92
There were no net charge requirements for ligand binding, but the binding site had both polar and apolar
domains. The apolar domain could accommodate branching on the carbon-3 of cystine.
The kinetic properties of lysosomal cystine transport have been loosely defined in at least two different
systems. In leukocyte lysosomes, the K m approximated 0.5 mM with respect to L-cystine, 41 and the V max
for egress was approximately 23 pmol half-cystine per unit of hexosaminidase per minute. 39
(Hexosaminidase is a lysosomal enzyme whose activity provides a denominator for expressing transport
rates per lysosome.) The Q 10 approximated 2.0 with an energy of activation of 11.4 kcal/mol. 41 In mouse
L-929 cells, the K m was 0.27 mM, and there appeared to be a component of cystine uptake that could not
be saturated. 92
Normal cystine countertransport, studied in leukocyte lysosomes, was relatively independent of the
extralysosomal sodium or potassium ion concentration. 41 However, cystine efflux was greatly enhanced
when lysosomal membranes were made permeable to potassium ions either by an ionophore such as
valinomycin, or by the presence of a permeant anion. 93 The potassium-valinomycin effects were present
in cystinotic lysosomes as well, suggesting that they were not mediated through the carrier system
deficient in cystinosis. Moreover, the valinomycin effect was not observed in fibroblast lysosomes, 94 and
valinomycin/potassium pretreatment did not enhance cystine egress from rat liver lysosomes. 95
Magnesium chloride did stimulate leukocyte lysosomal cystine transport in a concentration-dependent
fashion up to 5 mM at pH 5.5. 96
The interpretation of ATP effects on lysosomal cystine transport is complicated by the fact that ATP not
only provides energy but that it also effects lysosomal acidification through a divalent cation-dependent
proton pump. 97 Furthermore, different results and conclusions have emanated from investigations in
different cell systems, leaving final analysis for future studies employing artificially expressed CTNS
protein. For a detailed discussion of ATP-related work to date, see the previous edition of this chapter. 98
I-cell fibroblasts, which lack the Golgi enzyme necessary for placement of the mannose-6-phosphate
recognition marker on lysosomal enzymes (see Chap. 138), store cystine in their lysosomes. 99, 100 I-cell
granular fractions have prolonged half-times for cystine clearance, 38 perhaps because optimal cystine
carrier function requires lysosomal processing by enzymes deficient in I-cell disease.
Several miscellaneous properties of lysosomal cystine transport have been reported. Polyamines have
been shown to stimulate cystine egress from rat liver lysosomes. 101 Stearylamine enhances cystine efflux
from cystinotic lysosomes, probably through its detergent properties. 102 Cystinotic fibroblasts lose cystine
at above-normal temperatures, 103, 104 perhaps because of increased membrane fluidity or because
another carrier recognizes cystine at elevated temperatures. Lysosomal cystine transport does not appear
to be mediated by γ-glutamyltranspeptidase, because a patient deficient in this enzyme had normal
lysosomal cystine transport. 105
Finally, lysosomal cystine transport has been described in functional rat thyroid (FRTL-5) cells in
culture 106 and in S. cerevisiae yeast acidic vacuoles. 107
Mechanism of Cystine Depletion by Cysteamine

Cysteamine, or β-mercaptoethylamine (Fig. 199-1), is an aminothiol that, in 1976, was shown to rapidly
and extensively lower the cystine content of cystinotic fibroblasts. 108 It was suggested that cysteamine
reacted with cystine to form cysteine and cysteine-cysteamine mixed disulfide (Fig. 199-4). The cysteine
would leave cystinotic lysosomes freely, 35 perhaps via a specific lysosomal membrane carrier. 109 The
mixed disulfide would also exit the lysosome because its molecular mass was less than 220 daltons, the
accepted upper limit for free movement of amino acids and di- and tripeptides across the lysosomal
membrane. 110 Subsequent work demonstrated that because cysteine-cysteamine mixed disulfide
resembles lysine structurally and because cystinotic fibroblasts have an intact lysosomal transport system
for lysine, the mixed disulfide was transported across cystinotic lysosomal membranes in a
carrier-mediated fashion, by the intact lysine porter. 37 In fact, experiments in leukocytes demonstrated
that cysteine-cysteamine mixed disulfide was cleared at a significant rate from cystinotic granular
fractions, in contrast to cystine, which remained trapped inside the lysosomes. 111 These two studies
essentially verified the hypothesis put forth several years earlier concerning the mechanism of cystine
depletion by cysteamine. 108
Mechanism of cystine depletion by cysteamine. Cystine is stored inside the cystinotic lysosome because
the cystine carrier in the lysosomal membrane is defective. Cysteamine traverses the lysosomal
membrane by virtue of its neutral amine group or via a cysteamine carrier. The amine group acquires a
positive charge and is “trapped” within the acidic lysosome. Cysteamine then reacts with cystine,
producing cysteine and the mixed ...
Investigations in isolated human fibroblast lysosomes have now demonstrated that cysteamine is taken up
by a specific transport system. 112 It has a biphasic Arrhenius plot with a Q 10 of 1.2 between 27 and 35°C
and 2.2 between 17 and 26°C. The rate of uptake is maximal at pH 8.2 and at pH 5.0 is one-fiftieth of the
maximum. The system is specific for aminothiols or aminosulfides containing an amino group and a sulfur
atom separated by two carbon atoms. Thus, cystine depletion of cystinotic lysosomes utilizes specific
carriers for the entry of cysteamine, 112 exodus of the cysteine-cysteamine mixed disulfide via the lysine
transport system, 37 and exodus of cysteine, the other product of the intralysosomal reaction, probably by
a carrier system of its own. 109
Several other reagents have been investigated for their cystine-depleting ability, including many which
were enclosed in liposomes for presentation to cells. 113 Dithiothreitol lowered the cystine content of intact
cystinotic fibroblasts 114 and of leukocyte granular fractions, 111 presumably by penetrating the lysosome
and reducing cystine to cysteine. Ascorbic acid caused a 50 percent decrease in the cystine content of
cultured fibroblasts, perhaps by its effects on properties of the lysosomal membrane. 115 Other
compounds apparently act by producing cysteamine itself. Pantethine, which depletes intact cystinotic
fibroblasts 116 but not leukocyte granular fractions of cystine, 111 is degraded to cysteamine by
pantetheinase, 117 an enzyme present in human fibroblasts. 118 The aminothiol WR 1065, or
N-(2′-mercaptoethyl)-1,3-propanediamine, and WR 638, or phosphocysteamine, were also proposed to
produce cysteamine as the active cystine-depleting agent. 119, 120 Recently, mercaptoethylgluconamide
was shown to lower the cystine content of cystinotic cells, 121 again by its breakdown to the active
compound, cysteamine.
Cysteamine has other cellular consequences based upon the redox effects of its free thiol. An intact
intracellular redox potential is essential for normal cell functioning, and is crucial for the formation of
certain viral coat proteins. Cysteamine interferes with HIV replication and may also directly alter the
conformation of the gp120 coat protein, thus inhibiting viral transmission. Direct physicochemical effects of
cysteamine on critical membrane disulfides may also explain the activity of the free thiol as a topical
contraceptive. 122
Source of Lysosomal Cystine in Cystinosis

The intralysosomal cystine crystals in cystinotic cells are thought to form because of saturating
concentrations of cystine within lysosomes 25 rather than the phagocytosis of preformed crystals. 16 In
cultured cells, the source of intralysosomal cystine appears to be cystine itself in the presence of
exogenous cystine and to be protein catabolism in the absence of exogenous cystine. 123–125 When
exogenous cystine serves as the source of lysosomal cystine in cystinotic fibroblasts, 124, 126 it may enter
via two routes. 127 One is rapid, low-capacity, chloroquine inhibitable, and involves movement through the
plasma membrane, cytosol, and lysosomal membrane. The other is slow, high-capacity, stimulated by
chloroquine and low medium pH, and might involve pinocytosis, with fusion of pinosomes and lysosomes.
There is also evidence that cystine that enters fibroblasts is reduced in the cytoplasm to cysteine, 128
which could enter the lysosome by a known cysteine carrier in the lysosomal membrane. 109 Protein
catabolism also gives rise to lysosomal cystine; the lysosomal cystine content has been shown to vary
directly with the concentration in the medium of the cystine-rich protein, bovine serum albumin. 129 The
process consists of pinocytosis of proteins followed by proteolysis, the rate of which is normal in cystinotic
fibroblasts. 129, 130 Lloyd pointed out that cysteine could be the physiologic reductant in lysosomal
proteolysis facilitating reduction of intrachain disulfides. In this scheme, there would be no net increase or
decrease in the amount of disulfide within lysosomes, but the net result would be conversion of an
intrachain disulfide to a free cystine molecule. 131 Glutathione may 132 or may not 125 be a source of
lysosomal cystine in cystinosis. However, de novo cysteine synthesis through the cystathionine
β-synthase pathway has been shown not to be the source of stored cystine in cystinosis. 125, 133
We currently do not know why cystine is lost from cystinotic fibroblasts when the fibroblasts are placed at
acid pH, 134 in chloroquine-containing medium, 135 at an elevated temperature, 103 or when they are
labeled with [ 35 S]cystine and placed in cystine-free medium. This latter occurrence may be due to
exocytosis, because the kinetics of [ 35 S]cystine egress resemble those of tritiated sucrose and tritiated
mannitol, fluid-phase markers of endocytosis and exocytosis. 28
GENETICS
All forms of cystinosis, including the unusual variants (see “Cystinosis Variants” below), display autosomal
recessive patterns of inheritance, with a male/female ratio near 1.0. In North America, the incidence of
infantile nephropathic cystinosis is approximately 1 per 100,000 to 1 per 200,000 live births, with a carrier
frequency of roughly 1 in 200 in the general population. An estimated 400 to 500 children in the United
States have the disease, but ascertainment is suspected to be incomplete, with undiagnosed infants dying
of dehydration. The incidence is higher in certain subpopulations. The French province of Brittany, for
example, has an estimated incidence of 1 in 26,000, while in the rest of France, the incidence is 1 per
326,440. 136 The incidence rate of infantile and adolescent cystinosis in the Federal Republic of Germany
was approximately 1 per 179,000 live births; of 101 registered patients, 95 had infantile-type cystinosis, 5
had the adolescent type, and 1 had the adult type. 137 A recent study reported the frequency of cystinosis
in the West Midlands, United Kingdom, to be 1 in 46,564 among northwest Europeans, and 1 in 3,613
among Pakistanis. 138
Cystinosis is often considered a disease of fair-skinned individuals of European descent, but it is known to
occur in Blacks, Hispanics, and people of Middle Eastern descent, and has also been described in at least
one Chinese and several Japanese patients. It is likely that most cases of nonnephropathic (i.e., ocular)
cystinosis are never diagnosed, and thus one can only speculate on the incidence of this type of
cystinosis.
Only recently has the search for the cystinosis gene reached fruition. In 1995, the Cystinosis Collaborative
Research Group used polymorphic microsatellite repeat markers to map the gene for cystinosis to a 4-cM
region of chromosome 17p13 by linkage analysis. 44 The lod score for marker D17S1584, at a
recombination fraction of 0.01, was 10.30. The critical region was progressively narrowed, 139–141 and in
1997, a study of French Canadian cystinosis patients revealed strong linkage disequilibrium for D17S829,
a specific microsatellite marker in the region. 142 A physical map of the area surrounding this marker was
created using a cosmid/P1 artificial chromosome contig. STS analysis indicated that the gene segment
deleted in many cystinosis patients was 65 kb in size, and exon trapping followed by cDNA library
screening revealed the cDNA of the cystinosis gene CTNS. 45 Mutation analysis defining 11 small
mutations in cystinosis patients confirmed that this cDNA represented the cystinosis gene. 45 CTNS has 12
exons spanning 23 kb of genomic DNA. Its 2.6-kb mRNA codes for the 367-amino-acid protein cystinosin,
with homology to a 55.5-kDa C. elegans protein and to the yeast transmembrane protein ERS1. 45
Cystinosin has seven transmembrane domains, a GY dipeptide near the C-terminus, and eight potential
glycosylation sites.
The most common CTNS mutation, involving D17S829, consists of a deletion extending from intron 10
upstream 57,257 bases. 142a This was found in the homozygous state in 23 of 70 patients in the
British-French report, 45 and in 48 of 108 American-based patients. 91 Of 82 alleles bearing the 57-kb
deletion, 38 derived from Germany, 28 from the British Isles, and 4 from Iceland, suggesting that the
deletion arose in Germany prior to 700 AD. 91 The next most common mutation, present in 12 percent of
the 216 American alleles studied, was 753G → A (W138X). In all, over 30 other mutations have been
identified, 45, 91, 142b, 142c, 142d, 243b and in one study only 19 percent of patients failed to have one of their
mutations determined. The base changes include deletions, insertions, splice site, nonsense, and
missense mutations scattered throughout the gene’s various exons and domains (Table 199-2). Several
polymorphisms were also identified. 91 On northern blot analysis, all patients examined, whether
homozygotes or compound heterozygotes, displayed CTNS RNA expression in their cultured fibroblasts,
except for homozygotes for the 57-kb deletion. 91
Table 199-2: CTNS Mutations and Frequencies
CTNS Domain Mutation # of Alleles *
Exons 1–10 57-kb del 143 †
Leader sequence 357delGACT 12
371delT 1
397delTG 2
Transmembrane regions 753G → A 27
845G → A 2
857delAC 1
883T → C 1
985insA 2
1080delC 1
1253A → G 1
1261G → A 2
1261insG 1
1354G → A 1
1367TCGTCTTC → A 1
Nontransmembrane regions 479 + 1G 1
537del21bp 6
622G → T 2
651delTCAC 2
721C → T 3
900delG 3
901-1G → C 1
908del9bp 1
950delACG 2
952G → A 1
1033insCG 1
1035insC 2
1209C → G 2
1232G → A 1
* Of
356 alleles in 178 individual patients not known to be related. 45,91 Cell repository mutations 91
were not considered.
† This
includes one heterozygous patient whose deleted allele was ascertained by inheritance of
polymorphic markers. The remaining 71 patients were homozygous for the deletion.
A previous study in which somatic cell hybrids were prepared between cells from patients with different
types of cystinosis suggests that the various forms of cystinosis are allelic. 143 Moreover, inclusion of
cystinosis variant families in linkage studies contributed to the lod scores, rather than detracting from
them. 44 Finally, preliminary results indicate that intermediate and ocular cystinosis patients have
mutations in CTNS, but that these mutations differ from those of classical nephropathic cystinosis
patients. 144, 144a
CLINICAL FEATURES AND PATHOLOGY
Presentation and General Course (Fig. 199-5)

A recent article reviews the clinical course of cystinosis, 145 and a composite history for a typical child with
cystinosis was previously published. 146 As for most lysosomal storage disorders, patients with
nephropathic cystinosis are entirely normal at birth, except perhaps for lighter skin and hair pigmentation
than their sibs. Development proceeds normally until the second half of the first year of life, when an
affected infant generally fails to grow and gain weight, eats poorly, appears fussy, urinates and drinks
excessively, and suffers isolated or recurrent episodes of acidosis and dehydration. These findings all
result from renal tubular Fanconi syndrome; glucosuria may also eventually lead to a diagnosis of
cystinosis. For 55 patients seen at the NIH between 1960 and 1980, the median age at diagnosis was 20
months; for 44 patients seen between 1980 and 1992, the median age at diagnosis was 14 months. 147
The age at diagnosis is constantly decreasing because of increased physician awareness, but some
children still probably escape diagnosis when they succumb to severe dehydration during an acute
diarrheal illness.
Patients with nephropathic cystinosis. A, A 20-month-old girl with sparse blond hair and blue eyes. B, A
9-year-old girl on cysteamine for 7 years with well-pigmented hair but short stature. C, A 25-year-old
posttransplant patient with evidence of steroid effects. He later rejected his renal allograft and died of
peritonitis. (Courtesy of National Institutes of Health Clinical Center.)
The natural history of cystinosis after infancy dictates that an affected child will manifest normal
intelligence but continue to grow poorly. Photophobia usually, but not universally, develops. Renal
glomerular function is lost gradually, requiring renal transplantation at approximately 9 to 10 years of age.
The child will not have a predisposition to infections, although altered motility and adherence 148 and
increased leukotriene C 4 levels 149 have been reported in the phagocytic cells of children with cystinosis.
After kidney transplantation, renal function is normalized, but the inexorable accumulation of cystine in
other organs creates newly recognized threats to their proper functioning. 146
Renal Tubular Involvement

The kidney appears particularly susceptible to the adverse effects of cystine accumulation in cystinosis.
As early as 1965, three stages of renal damage were recognized in cystinosis: tubular injury with failure to
reabsor; tubular insufficiency with decreased para-aminohippuric acid clearance; and glomerular
failure. 150 Impaired tubular reabsorption, known as the renal Fanconi syndrome, apparently correlates
with the “swan-neck” deformity of the proximal convoluted tubule. 17 The tubules of a cystinosis patient’s
kidneys have appeared disorganized and poorly developed even prior to the onset of frank Fanconi
syndrome. 151 Cystinosis represents the most common identifiable cause of renal tubular Fanconi
syndrome in children, although tyrosinemia, Wilson disease, Lowe syndrome, galactosemia, and glycogen
storage disease are part of the differential diagnosis.
The Fanconi syndrome results in excessive urinary losses of glucose, amino acids, phosphate, calcium,
magnesium, sodium, potassium, bicarbonate, carnitine, water, and, undoubtedly, other small molecules
yet to be identified. Children with cystinosis may initially receive a diagnosis of Bartter syndrome,
nephrogenic diabetes insipidus, or pseudohypoaldosteronism. 152–154 A “tubular” proteinuria, in which
proteins of molecular weight 10 to 50,000 are excreted in fiftyfold normal amounts, can also develop. 155
Total protein excretion can be up to 5 g per day. 156 Microscopic hematuria is occasionally present. Renal
calculi of urate and calcium oxalate have been reported, 157, 158 and nephrocalcinosis has been found in
association with increased calcium excretion in cystinosis patients. 159 This medullary nephrocalcinosis
was documented in 26 of 41 patients age 2 months to 15 years. 160 The mean age of the affected children
was 9.4 ± 3.5 years, compared with 5.1 ± 3.8 years for the 15 children without nephrocalcinosis
(p < 0.005). The nephrocalcinosis, which does not appear to impair glomerular function, was associated
with vastly elevated levels of urinary calcium and phosphate, the consequence of renal Fanconi syndrome
combined with mineral supplementation.
Although blood glucose levels are normal in cystinosis, glucosuria and polyuria can lead to the mistaken
diagnosis of juvenile-onset diabetes mellitus. The polyuria consists of daily excretion of 2 to 6 liters of
dilute urine (less than 300 mOsmol/liter), and may contribute to persistent enuresis or may be
life-threatening in an infant suffering acute gastroenteritis. Dehydration in such a patient is rapid and can
be associated with a mild chronic fever. Acidosis can be profound due to renal losses of bicarbonate.
Hyponatremia and hypokalemia, with its risk of arrhythmias, also occur. Muscle weakness due to
hypokalemia has led, in some instances, to inappropriate muscle biopsy. Hypocalcemia, and occasionally
hypomagnesemia, can result in tetany, especially when acidosis is acutely reversed by alkali therapy or
when phosphate supplements bind ionized calcium. Phosphaturia leads to hypophosphatemic rickets with
typical metaphyseal widening, rachitic rosary, frontal bossing, genu valgum, and failure to walk. Elevated
heat-labile serum alkaline phosphatase levels reflect active rickets. Vitamin D metabolites are normal in
cystinosis. 161 A generalized aminoaciduria 162 results in excretion of, on average, over 1 mmol/kg/day of
21 measurable amino acids; this is over tenfold the normal amino acid excretion. 163 The mean fractional
excretions of individual amino acids vary widely, 164 ranging from 0.10 for arginine to 0.71 for histidine; 165
normally, 94 to 99 percent of each amino acid is reabsorbed. Carnitine, a small molecule required for
transport of free fatty acids into mitochondria for subsequent energy production, is normally 97 percent
reabsorbed. However, because of their Fanconi syndrome, cystinosis patients reabsorb only 70 percent of
their carnitine, resulting in plasma and muscle carnitine deficiency. 163 Consequently, lipid droplets
accumulate in the muscle, which may appear weak and poorly developed. The full ramifications of the
Fanconi syndrome in cystinosis have not yet been determined, but they include the failure to thrive
characteristic of this disorder.
Glomerular Damage
The glomerular deterioration that provides the clinical hallmark of cystinosis proceeds inexorably in
untreated patients. Pathologically, the cystinotic kidney manifests different stages of destruction 166 with
giant-cell transformation of the glomerular epithelium, 167 hyperplasia and hypertrophy of the
juxtaglomerular apparatus, 15, 89 and occasional “dark” cells and cytoplasmic inclusions. 65 The ultimate
result, however, remains a classic end-stage kidney with scarring and fibrosis, chronic interstitial nephritis,
and tubular degeneration. 81, 168 Crystals, identified as L-cystine, 19 are abundant, but renal stones do not
form, as in cystinuria. Clinically, most patients have proteinuria and many have granular casts and
microscopic hematuria. Measured creatinine clearances fall monotonically from infancy in untreated
patients. 169 Occasionally, renal failure occurs as early as 1 to 3 years of age, 170, 171 but renal reserve
generally prevents the serum creatinine from rising above 1.0 mg/dl before approximately 5 years of age.
As for other renal disease, 172 the reciprocal of serum creatinine decreases linearly with age, predicting
renal failure in cystinosis at 9.1 169 or 10.7 173 years of age. For 205 European patients, serum creatinine
versus age curves provide standards for the natural history of renal demise; 174 the mean age of renal
death was 9.2 years. 175 Many patients approaching renal failure continue to waste large volumes of fluids
and electrolytes despite low filtration rates. In others, the Fanconi syndrome appears to improve with the
reduced filtration. Some patients have unexplained plateaus in their renal function lasting months to years;
others suffer a rapid deterioration of renal function with the onset of an acute infection, acute
poststreptococcal glomerulonephritis or, in infants, hypoperfusion secondary to dehydration. Cystinosis
patients with uremia can die in congestive heart failure.
Growth
Growth retardation represents a significant part of the clinical picture of nephropathic cystinosis, yet it
does not commence in utero. Length and weight are normal at birth. During the first year of life, linear
growth begins to decrease. Height falls to the third percentile by 1 year of age. In patients who do not
receive cystine depletion, growth proceeds at only 50 to 75 percent of the normal rate, so that an
8-year-old patient has the height of a normal 4-year-old. 176 Typically, height velocity is two to three
standard deviations below the mean for age when the glomerular filtration rate is above
20 ml/min/1.73 m 2 . 177 Bone age follows height age, which soon lags years behind chronologic
age. 146, 178, 179 Because height and weight are equally delayed, the children appear proportional except
for a relative macrocephaly caused by sparing of head circumference.
Growth and final height of cystinosis patients after renal transplantation is extremely variable. 89 Mean
heights for posttransplant patients age 10 to 18 years are 20 to 30 cm below the fiftieth percentile for
age. 163 Of 36 patients age 18 to 34 years seen at the National Institute of Child Health and Human
Development (NICHD), 181 the tallest male was 170 cm and the shortest was 129 cm (mean ± SD,
148 ± 10 cm); the mean was approximately 30 cm below the average normal adult height. Among females,
the range was 117 to 149 cm, with a mean ± SD of 137 ± 10 cm, or 26 cm below the mean adult height.
Mean values for 33 French patients age 18 to 34 years were 143 cm for males and 128 cm for
females. 182 While children transplanted before adolescence have some chance of realizing a growth spurt
and achieving near-normal height, this prospect appears remote for patients grafted after 16 years of age,
despite a bone age several years delayed. 179 One study found catch-up growth after renal transplant in
cystinosis patients receiving cyclosporine A and low-dose prednisone, but not among those receiving
azathioprine and high-dose prednisone. 177
The pathogenesis of the growth retardation in cystinosis remains unresolved. Children with renal failure
due to other causes generally do not show the profound impairment of growth exhibited by patients with
cystinosis. Renal failure, chronic acidosis, and renal rickets result in growth delays, but even cystinosis
patients without these complications grow poorly. The common feeding problems in children with
cystinosis 183 may contribute to failure to thrive. In addition, cystine storage in various organs, including
growth plates of long bones and developing myofibrils, may inhibit growth, which improves with chronic
cystine depletion. 176 Single growth hormone measurements 184 and somatomedin-C levels 178 are normal
in patients with cystinosis.
Ocular Damage
Cystinosis eventually affects most of the structures 185 and many of the functions of the eye, but with
variable rates of progression. Several reviews have detailed the early 186, 187 and late 74, 89, 179 ocular
findings in cystinosis.
Retina.
A characteristic peripheral retinopathy, consisting of a patchy depigmentation of the retina with pigment
clumps of various sizes, typifies nephropathic cystinosis. 188 This finding is not present at birth, although
vacuolization of retinal pigment epithelial cells has been reported in a 21-week cystinotic fetus. 189 A
pigment retinopathy has been reported in a 5-week-old girl who was subsequently diagnosed as having
cystinosis. 76 Despite the “blond fundus” resulting from degeneration of the retinal pigment epithelium,
visual acuity, visual fields, night vision, and electroretinography have been normal in young children with
cystinosis. 187 But posttransplant patients, whose retinas have accumulated cystine for one to three
decades, exhibit a disconcerting frequency of visual impairment. Although visual acuity was subjectively
normal in a series of 10 patients age 11 to 19 years, electroretinography was abnormal in 1 individual. 190
Of 16 patients in a French study, 3 exhibited marked visual impairment and 8 had abnormal
electroretinography. 89 In a survey of 80 patients over the age of 10 years in North America, one-third had
decreased visual acuity. 191 It is clear that the frequency and severity of visual impairment increase with
age. Of six patients over 30 years of age examined at the National Eye Institute, five had visual acuities of
20/200 or worse, with color vision and dark adaptation deficits as well. 179 Electroretinography confirmed
the clinical findings in affected patients, 74, 179 and retinal crystals were documented by photography in
one individual. 74 Color and night vision deficits appear to precede problems with acuity.
Cornea.
Corneal crystals, first described in cystinosis in 1941, 192 are pathognomonic of the disorder when seen on
slit-lamp examination by a trained ophthalmologist. Descriptions of the pathology of the corneal tissue in
cystinosis are numerous. 186, 187, 193–195 Fusiform crystals involve the anterior portion of the central cornea
but occupy the full thickness of the peripheral cornea. 73, 187 They are absent at birth and at 3 months of
age, 73 but are generally present by 1 year of age. 187 A patchy pattern is occasionally observed between
1 and 2 years of age, and the presence of crystals not apparent on slit-lamp examination in a moving
infant can sometimes be documented by photography. By 3 or 4 years, cystinotic corneas are packed with
crystals, and by 10 to 20 years of age, corneas often develop a characteristic haziness. 74 At this time,
exquisitely painful corneal erosions, documented by fluorescein testing, can recur several times a month
and seriously interfere with normal activities. 74, 179, 196 Decreased tearing, documented by Schirmer
testing, 197 can exacerbate this condition. In one patient whose cornea was examined
immunohistologically, an inflammatory component appeared to be involved. 198 Of 50 patients over 16
years of age examined at the National Eye Institute, 8 had some degree of band keratopathy, with one
15-year-old girl exhibiting such plaque formation that she was blind to all light perception. 197 Corneal
thickness has been reported increased in cystinosis. 199 A keratopathy has been described in rabbits fed
L-cystine.
200
Photophobia of variable onset produces various degrees of discomfort in children with cystinosis, 74, 201
who often avoid sunlight. The photophobia probably results from reflections of light off corneal and
conjunctival crystals, because it decreases with cysteamine eyedrop therapy 197 and progresses in
severity if untreated. 74
Conjunctiva.
The conjunctiva and uvea contain birefringent hexagonal and rectangular crystals 73 shown by x-ray
diffraction studies to be made of L-cystine. 195 These can produce a ground-glass appearance on slit-lamp
examination, but do not cause inflammation. 187 Electron microscopy of conjunctival tissue has been used
to demonstrate the lysosomal location of the crystals. 202 Cystine measurements in conjunctival biopsies
have been suggested for the early diagnosis of cystinosis, 203 but leukocyte assays are less invasive.
Other Ocular Tissues.

Cystine crystals are present in the uvea and sclera of cystinosis patients. 187 The irides also contain
crystals, especially in older individuals, 74 and crystals have been documented overlying the lenses of
posttransplant patients. 74, 196 The presence of crystals in these locations may give rise to tissue reactions
which result in posterior synechiae, observed in nine National Eye Institute patients 16 to 34 years
old. 74, 179, 197 This complication may in turn lead to glaucoma, which has been observed in two patients
19 and 27 years old. 74, 179, 202 Refractory blepharospasm, apparently a result of constant guarding
against painful photophobia, has been found in a few older individuals. 74, 179
Endocrine Involvement
Children with cystinosis frequently develop primary hypothyroidism, with atrophy and crystal formation in
follicular cells. 77 This apparently reduces the thyroid’s functional reserve and causes compensated
hypothyroidism, that is, an increase in thyrotropin (TSH) prior to the onset of frank hypothyroidism. 184, 204
In particular, the α subunit of TSH is often elevated. 205 Hypothyroidism clearly represents an age-related
phenomenon. In one study, 3 of 15 patients examined before age 13 years were clinically hypothyroid. 77
Fifteen of 27 French children of all ages with cystinosis were hypothyroid. 89 More than 70 percent of 80
North American patients over 10 years of age required thyroid replacement, with an average age of 10
years at the initiation of therapy. 191 Hypothyroidism in cystinosis may be associated with pituitary
resistance to thyroid hormone, 206 and histologic studies of cystinotic pituitary glands have revealed
occasional hyperplasia of thyrotrophs and refractile crystals. 77 However, growth hormone, 184
somatomedin-C, 178 and cortisol response to ACTH 184 appear normal in children with cystinosis.
The pancreas may also be affected by long-standing cystine accumulation. Although nonsuppressible
insulinlike activity is normal in young children with cystinosis, 184 several patients have developed
insulin-dependent diabetes mellitus after the age of 10. 68, 89, 207 Poor glucose tolerance results from
impaired insulin production, 68 and is exacerbated by antirejection steroid therapy. Diabetes mellitus has
been reported in a 13-month-old infant with cystinosis, 208 and β-cell hyperplasia has been found in
cystinotic pancreases examined postmortem. 209
Females with cystinosis undergo pubertal events in a normal sequence, 179 but at ages which range from
normal to late, that is, 16 to 17 years of age. To date, most affected females have undergone a renal
transplant before puberty, meaning that uremia, or immunosuppressive therapy, or both, has interfered
with normal development. Nevertheless, virtually all the affected females eventually progress, 180 and one
20-year-old woman with cystinosis and a renal transplant gave birth to a normal boy in late 1986. 80
Male patients with cystinosis have delayed puberty (with a normal sequence of progression), again with
some influence exerted by renal failure and transplantation. 210 None of 10 male patients age 15 to 28
years studied at the NICHD reached Tanner stage 5 of pubertal development, but several adult males in a
German study did complete sexual development. 177 Three males in the NICHD study had decreased
testosterone and seven had elevated FSH and LH levels. 210 In a French study, adult male patients
exhibited hypogonadism, with high FSH and LH levels in 9 of 11 individuals tested. 182 These findings
suggest primary hypogonadism, and the occurrence of crystals and fibrosis in the testes of a 22-year-old
patient is consistent with this diagnosis. Older male patients can experience erections, but three patients
who produced a semen sample all proved to be azoospermic. 156, 210 To our knowledge, no cystinosis
patient has fathered a child, but this may change as treated patients reach adulthood with normal
testicular function.
Myopathy
Although the muscle was long considered spared in cystinosis, it recently became apparent that the
continued accumulation of cystine in this tissue leads to structural changes and functional impairment. Not
only do cystinotic myotubes in culture store cystine, 211 but the cystine content of biopsied muscle
increases with age to values 1000 times normal. 79, 89, 90 The clinical characteristics of the muscle
involvement in cystinosis were first recognized in a 22-year-old man with generalized muscle wasting. 79
This posttransplant patient developed hypophonia and dysphagia at age 20, progressed in weakness and
wasting, and died of aspiration 2 years later. He had normal nerve conduction studies, but
electromyography showed low-amplitude brief-duration polyphasic motor-unit potentials consistent with a
myopathy. Muscle biopsy sealed the diagnosis with the appearance of type I fiber atrophy, variation in
fiber size, and numerous ring fibers. Cystine crystals were apparent in fibroblastoid cells in the perimysial
and endomysial spaces adjacent to muscle fibers. 79 To date, at least five other patients seen at the NIH
have had clinically documented myopathies, supported by electrophysiologic evidence. 212 One
21-year-old woman with severe wasting of her hand muscles (Fig. 199-6A) underwent a biopsy of one of
her abductor digiti minimi muscles, which showed striking vacuolization and a cystine concentration more
than one hundredfold elevated. 212 A case of myopathy and corneal crystals reported in the ophthalmic
literature appears to represent cystinosis with muscle involvement. 213
Late complications of nephropathic cystinosis. A, Right hand of 21-year-old posttransplant patient with a
distal myopathy. Note wasting of thenar and hypothenar eminences and interosseous muscles. Fingers
are held in partial flexion due to weakness. B, Barium study of swallowing in a 22-year-old posttransplant
patient. Residual barium coats the pharyngeal wall and remains in the valleculae (arrow). Some barium
has penetrated the laryngeal ve...
The severe swallowing difficulties observed in older cystinosis patients probably result from impaired
muscle function. 214 Affected individuals have decreased tongue and lip strength, hypophonic speech, and
abnormal oral structure and anatomy. Swallowing studies (Fig. 199-6B) show pooling of barium in the
valleculae and piriform sinuses, and some penetration of the laryngeal vestibule, with a significantly
increased duration of swallowing. The severity of oral motor dysfunction increased with age. One patient
died of his swallowing difficulty, 79 and at least two others are seriously affected.
In a recent study of pulmonary function in cystinosis, 215 11 of 12 adult patients (mean age 28 ± 4 years)
had restrictive ventilatory defects, with a mean forced vital capacity of 58 ± 13 percent of predicted. These
patients had not received significant chronic cysteamine therapy (see “Therapy” below), and the
pulmonary findings were attributed to weak accessory chest and diaphragmatic muscles. Patients under
age 20, as a rule, had no pulmonary deficits. It has been suggested that pulmonary cystine crystals can
be detected radiographically, 216 but no evidence for this is available. Cardiac muscle has not been
extensively examined for abnormal structure, function, or cystine storage in cystinosis. A single report
describes elevated myocardial cystine levels and cardiac failure in a 31-year-old posttransplant cystinosis
patient. 217
Nervous System Involvement

Although the central nervous system has also been considered spared in cystinosis, this may be true only
early in the disease. Cystine storage is limited in young patients, 87 but one 25-year-old woman
accumulated large quantities of cystine in all portions of her central nervous system, 88 and a 28-year-old
man had cystine crystals within white matter parenchymal cells. 218 The clinical correlates of central
nervous system storage include cerebral atrophy on CT scan, seen in 3 cystinosis patients in chronic
renal failure; 219 in 7 of 9 220 and 11 of 17 posttransplant patients; 180 in a group of 10 cystinosis patients
with neurologic symptoms such as seizures, tremor, mental retardation, or pyramidal syndrome; 221 in 13
of 14 unselected cystinosis patients age 13 to 25; 222 and in 10 of 11 cystinosis children and
adolescents. 223 Cerebral cortical atrophy can be observed in pediatric patients with end-stage renal
disease, 224 but the frequency in cystinosis seems excessive, and one study controlled for this. 221 Other
cerebral involvement in cystinosis includes nonabsorptive hydrocephalus, 225 demyelination of the internal
capsule and brachium pontis, 82 and cystic necrosis with calcification, spongy change, and
vacuolization. 218 The patient with the latter problem, a man in his mid-twenties with a renal transplant for
14 years, had difficulty swallowing, slow speech, loss of recent memory, extremity weakness, and a gait
disturbance confining him to a wheelchair. 218, 222 Despite the cerebral atrophy seen on CT scan, most
cystinosis patients have normal neurologic examinations. 222 Neurophysiologic testing of the peripheral
nervous system is normal in cystinosis. 226
Hepatic and Gastrointestinal Complications

Hepatomegaly has been reported in 7 of 16 dialysis and transplant patients with cystinosis 89 and in 42
percent of 80 cystinosis patients over the age of 10. 191 Many children under age 5 also have
hepatomegaly, whose etiology is unknown. In general, it is not associated with elevated serum liver
enzymes or clinical abnormalities. Esophageal varices in two patients, 89 and bleeding gastric varices in
another, 227 did result from portal hypertension. Hypersplenism syndrome has been seen in occasional
patients, 89, 179 and the incidence of splenomegaly among patients over age 10 is 27 percent. 191
Liver pathology has demonstrated crystals, 66 hepatic veno-occlusive disease, 226, 227 and portal
hypertension with fibrosis, 228 but not cirrhosis. 89 The liver has a normal acinar architecture with
hypertrophy of Kupffer cells and, to a lesser extent, portal macrophages as a result of cystine crystal
formation. 229 The affected Kupffer cells are haphazardly distributed, but may be clustered around terminal
hepatic venules in zone 3. There is usually no inflammatory response and little or no fibrosis.
Hepatocytes, perisinusoidal lipocytes (Ito cells), bile ducts, and blood vessels usually show no pathologic
changes. 229
Cystine crystals also occur in the appendix, 71 rectal mucosa, 69 and intestinal mucosa. 70 Their presence
may contribute to the morning nausea and vomiting observed among some children with cystinosis, many
of whom are also poor eaters with penchants for hot, spicy foods. 146 One 7-year-old boy with severe
cystinosis has been diagnosed with ulcerative colitis, 230 and a 17-year-old woman, 231 as well as a
21-year-old man, 156 had objective evidence of pancreatic exocrine insufficiency.
Other Clinical and Laboratory Abnormalities

Caucasian (not Hispanic or Black) patients with cystinosis have skin and hair pigmentation that is
noticeably lighter than the pigmentation of their unaffected sibs. We speculate that pigment formation may
be impaired in the melanosomes, which are the melanocyte counterparts of lysosomes. Deficits of
short-term visual memory, 232 tactile recognition, 233 spelling, 234 and arithmetic 235 have been reported in
children with cystinosis, although IQ values are in the normal range. 235 Young patients with cystinosis
have average intelligence and school performance. 236 Psychosocial problems occur because of their
chronic illness, and adjusting to a life of short stature often proves difficult. 146 Some children avoid school
and others fail to extricate themselves from dependence on their parents.
Most children with nephropathic cystinosis display an inability to produce a normal volume of sweat,
although sweat electrolyte concentrations are normal. 237 This deficiency results in heat intolerance and
avoidance, flushing, hyperthermia, and vomiting in small children. The cause is unknown. Stimulated
salivary flow rates were also decreased below the normal range in 10 of 18 cystinosis patients tested. 238
Intraoperative hyperthermia occurred in a child with cystinosis, 239 and feeding problems are common in
patients with cystinosis. 183 Polyneuropathy and pulmonary fibrosis have been reported in individual
posttransplant patients. 67, 240
For reasons that remain mysterious, several laboratory values are often chronically elevated in cystinosis,
including the sedimentation rate, total serum cholesterol (including VLDL and HDL subfractions), and
platelet count. 146, 179 The platelet count normalizes after renal transplantation. 179 A mild anemia
becomes severe with the onset of uremia, with a hematocrit of 15 to 20 percent accompanying a serum
creatinine of 3 to 8 mg/dl. The anemia, not due to iron deficiency, may result from decreased
erythropoietin production by a damaged kidney and, later, from uremia. Posttransplant patients have
normal hematocrits. 179
Cystinosis as an Adult Disease

Renal allograft procedures have changed the face of cystinosis from a fatal childhood disease followed by
pediatric nephrologists to an adult disorder challenging internists and other specialists. The imprint of
cystinosis appears immediately on the prematurely aged, jowled faces of young adults, who often have
slow, raspy speech, 156 and almost always have short stature. 179 The associated problem of poor
self-image is exacerbated in males by the prospect of infertility. Medical catastrophes are also threatening.
One enigma of cystinosis is why certain patients suffer severe involvement of a single organ, with sparing
of other systems, and other patients suffer complications of a different organ system. Of 36 adult patients
seen at the NIH prior to 1993, 181 7 were deceased, 5 were legally blind, 3 others had poor vision in one
eye, 12 had a distal myopathy, 21 had swallowing abnormalities, 8 had cerebral calcifications, and 31
required thyroid hormone replacement. Only 11 were receiving adequate cysteamine therapy (see
“Therapy” below). In a similar French study of 33 adult patients, 182 6 were deceased, 5 were blind, 2 had
a distal myopathy, 7 manifested encephalopathy, 5 were insulin-dependent diabetics, and 27 required
thyroid replacement. Only 5 were receiving oral cysteamine therapy. Remarkably, despite their medical
complications, many of the adults engaged in valuable activities and gainful employment.
Heterozygotes
There are no published reports of any heterozygote for cystinosis having cystine crystals in any tissue or
cell, or exhibiting any clinical manifestations of the renal Fanconi syndrome. Nevertheless, their
polymorphonuclear leukocytes contain an increased amount of nonprotein cystine, 241 and peripheral
leukocytes of obligate heterozygotes exhibit approximately half-normal rates of lysosomal cystine
egress 39 and countertransport. 42 Surprisingly, the free-cystine content of cultured skin fibroblasts from
obligate heterozygotes is not significantly different from that found in normal control fibroblasts. 143
DIAGNOSIS
Postnatal
The first individual diagnosed as having nephropathic cystinosis in a family generally acquires the
diagnosis because of suspicion aroused by the presenting renal abnormalities. The diagnosis is confirmed
by measuring the white blood cell cystine content. Leukocytes are prepared from as little as 3 ml of
heparinized blood by acid citrate-dextran sedimentation, followed by hypotonic lysis of erythrocytes. 242
Cystine is then measured either with an automated amino acid analyzer using column chromatography or
by using a specific cystine-binding protein in an isotope dilution assay. 64, 243 In normal control individuals,
the cystine content of mixed leukocyte preparations is less than 0.2 nmol half-cystine per mg protein. In
infantile nephropathic cystinosis, the value averages approximately 8 nmol half-cystine per mg protein
(see reference 98 for references). In other forms of cystinosis the value may be lower, but is generally
greater than 1 nmol half-cystine per mg protein.
Cystinosis can be diagnosed immediately by ophthalmologic examination, revealing the typical crystalline
keratopathy in children over 1 year of age by use of a slit-lamp. The diagnosis can also be made by
examination of a bone marrow aspirate with phase microscopy, where the hexagonal and monoclinic
cystine crystals are obvious under crossed polarizing prisms (see reference 98 for references). In general,
however, patients should be spared invasive biopsies and aspirations, if possible.
The first case of ocular cystinosis in a family (see “Cystinosis Variants” below) is always detected by an
ophthalmologist who is doing a slit-lamp examination for some other reason. Again, the diagnosis can be
verified by white blood cell cystine assay.
There is no newborn screening program for cystinosis because of the labor-intensive nature of current
diagnostic tests.
Prenatal
Prenatal diagnosis can be performed on either cultured amniocytes following amniocentesis or cultured
chorionic villi by direct measurement of the intracellular free-cystine. A previous edition of this chapter
gives specific values and references. 98 Like cultured skin fibroblasts, cystinotic amniocytes and villus cells
store 50 to 100 times the normal concentration of cystine (see Table 199-1). DNA diagnostic techniques
may soon be available as well, especially for families in whom the proband is homozygous for the 57-kb
deletion in CTNS. 243a, 243b The amniotic fluid cystine concentration is normal in affected
pregnancies. 98, 189
Because of the success with cysteamine therapy (see “Therapy” below), many families now refuse
prenatal diagnosis but ask that the diagnosis be made immediately at birth so that treatment with
cysteamine bitartrate can be started as soon as possible. This is done by measuring the cystine content of
the placenta and/or white blood cells made from cord blood (see reference 98 for references). DNA
diagnostic techniques may soon be available for early diagnosis.
Heterozygotes
Leukocytes from obligate heterozygotes for cystinosis contain, on average, four to five times more
free-cystine per milligram of protein than leukocytes from normal control individuals. 20, 241 However, when
mixed populations of leukocytes are measured, about 10 percent of heterozygotes have values that fall
into the normal range. Heterozygote detection is more accurate when cystine is measured in
polymorphonuclear cells because most of the cystine is found in these cells and monocytes, and relatively
little in the lymphocytes. 85, 241 In the future, it may be easier to determine heterozygosity by molecular
techniques.
THERAPY
Symptomatic
Patients with cystinosis develop the renal Fanconi syndrome early in life with attendant renal tubular
losses of glucose, water, sodium, potassium, bicarbonate, phosphorus, and carnitine. Severe electrolyte
imbalances due to renal losses of water and electrolytes can cause fatal dehydration, particularly during
summer months and during episodes of gastroenteritis. Children with cystinosis may have extreme
polyuria secondary to their renal tubular damage, so that free access to large amounts of water is
essential during both day and night. Urinary losses of bicarbonate and electrolytes are replaced orally.
Progressive urinary losses of phosphate lead to rickets and generally require oral phosphate replacement,
with vitamin D supplementation to enhance gastrointestinal absorption of phosphate. The usual form of
vitamin D given these patients in the United States is 1,25-dihydroxycholecalciferol. A typical dose might
be 0.25 µg per day, but the dose must be individualized for each patient. Details of management have
been published previously. 98, 146
Many European medical centers find indomethacin extremely helpful in managing children with
cystinosis. 244–247 Properly used, it markedly reduces abnormal urinary losses. 248 The decreased need for
water ingestion may lead to an increased appetite and improved growth. 249 The dose of indomethacin (2
to 3 mg/kg/d) is individualized for each patient so as not to decrease the glomerular filtration rate. Any
decrease in GFR appears to be reversible when the drug dosage is reduced. 250 The mechanism of action
of indomethacin appears to be related to inhibition of prostaglandin synthesis. 247, 248 A recent
double-blind trial comparing 2 mg/kg/d of indomethacin to placebo found a small but significant reduction
in urine volume in the patients receiving indomethacin. 251 The most impressive finding, however, was that
most families believed their child was receiving the active drug because of a placebo effect. Children in
both groups ate better and had impressive gains in growth. A weakness of the study was that 2 mg/kg/d
was probably too low a dose for optimal effect in many patients.
Carnitine deficiency due to Fanconi syndrome can be treated with oral L-carnitine replacement. 163 Plasma
carnitine levels return promptly to normal, but because of enormous ongoing urinary losses, the muscle
compartment takes years to replete. 252, 253 A mean dose of 92 mg L-carnitine/kg/d, given to six infants for
an average duration of 5 years, maintained their muscle free-carnitine in the normal range, but strength
was not assessed. 253
As renal failure supervenes, the basic aspects of medical care are similar to those for any uremic patient.
Care must be taken to properly manage serum concentrations of calcium, phosphate, and potassium.
However, cystinosis patients have some unique problems. They often develop hypothyroidism by the end
of the first decade of life, 184, 191 but respond well to standard doses of L-thyroxine. Similarly,
insulin-deficient patients are benefited by insulin therapy. 68 As described below, cystine-depletion therapy
with cysteamine not only promotes growth and stabilizes renal function, but also prevents
hypothyroidism. 254
Renal Allografts
The natural history of infantile nephropathic cystinosis treated symptomatically is one of unremitting
progression of glomerular damage, eventually leading to death in uremia before puberty. In a large
European study, the mean age of “renal death” was 9 years. 175 Once uremia ensues in cystinosis,
dialysis or renal transplantation becomes essential. Hemodialysis of a boy with cystinosis was reported in
1966 255 and rapidly became part of the standard of care for uremic patients. It has recently been
supplanted in some areas by peritoneal dialysis, which can be continuous or intermittent, inpatient or
ambulatory. Dialysis represents a temporizing measure for patients awaiting renal transplantation.
Because the primary abnormality leading to renal failure in cystinosis is a genetically determined defect of
the intracellular environment, cells without this genetic defect that are transplanted into a cystinosis patient
do not accumulate intralysosomal cystine. This knowledge, and the success of the procedure, led to the
widespread use of transplantation in cystinosis patients. 89, 175, 179, 180, 256–263 Indeed, renal
transplantation in cystinosis patients has been more successful than renal transplantation in children with
other chronic renal diseases. 89, 148, 264 One life-table analysis of kidney allografts in cystinosis patients
revealed a 50 percent cadaveric graft survival rate 9 years after transplantation. 181 Transplanted kidneys
do not develop the series of functional changes of cystinosis, 256, 257 but they may reaccumulate cystine,
which electron microscopic studies suggest is largely, and perhaps entirely, confined to interstitial and
mesangial cells, presumably of host origin. 265 This phenomenon occurs in both heterozygous and
cadaver donor kidneys. Despite theoretic concerns that heterozygote donor kidneys might be more prone
than cadaver kidneys to cystine reaccumulation, 258 there is no evidence for this, and heterozygotes are
routinely accepted as kidney donors. Unfortunately, despite successful renal transplantation, severe
late-onset symptoms have occurred in nonrenal tissues in most of these patients. 181, 266
Specific Treatment to Reduce Cystine Storage

Attempts to deplete cystinotic cells of cystine by dietary restriction of cystine and methionine, or use of
drugs such as penicillamine, dithiothreitol, or ascorbic acid, have been described in earlier editions of this
text. 98 None of these approaches was successful.
Oral Cysteamine Therapy.

In contrast to the above experiences, the drug cysteamine (β-mercaptoethylamine), whose mechanism of
action has been described (see “Mechanism of Cystine Depletion by Cysteamine” above), has been very
effective in removing cystine from cystinotic cells and protecting cystinosis patients’ organs from
progressive damage. Earlier studies with cysteamine 108, 176, 267 are reviewed elsewhere. 98, 268 The
United States Food and Drug Administration approved cysteamine bitartrate capsules (Cystagon) for use
in cystinosis in August 1994. 269
Because cystinosis patients now range in age from infancy to over 40 years, it is best to express the dose
of cysteamine in terms of body surface area. Cysteamine, a free thiol, has the odor and taste of rotten
eggs, but most patients can tolerate a daily dose of 1.3 g/m 2 . This is given in divided doses, every 6 h.
For patients just starting cysteamine, it is important to begin at a very low dose and slowly increase the
dose to the expected final amount over a 4- to 6-week period. In early use of cysteamine, three patients
whose cysteamine dose was abruptly started at up to 70 mg/kg per day experienced a
Stevens-Johnson-like rash, central nervous system disorientation and lethargy, or neutropenia, all of
which resolved on discontinuing the drug. 270 With gradual incremental dosing, the only significant side
effects have been nausea and vomiting, which has been observed in approximately 14 percent of
patients. 176 A recent study found that cystinosis patients who receive cysteamine experience significant
increases in both serum gastrin concentration and gastric acid production. 271 This may play a role in the
gastric distress that some patients experience when taking cysteamine.
In 1992, 30 years’ experience involving 76 cystinosis patients at the National Institutes of Health was
reviewed. 169 Over 2000 24-h urines were collected, and creatinine clearances were measured. Patients
who never received cysteamine lost renal function monotonically, reaching renal failure at 9 to 10 years of
age. Seventeen patients were considered well treated with oral cysteamine, because they began
treatment prior to age 2 years and achieved good leukocyte cystine depletion. These children, selected
without knowledge of their ultimate renal function results, exhibited the same, very slow decline in
reciprocal serum creatinine that normal individuals display. The well-treated patients were predicted to
maintain adequate renal function past 25 years of age. Moreover, they exhibited an increase in creatinine
clearance in the first 3 years of life, which is consistent with the natural growth of renal function during this
period (Fig. 199-7). This increase in glomerular filtration rate translated into vastly prolonged maintenance
of renal function later in life, emphasizing the value of early therapy and bolstering hope that some
patients may never require a renal allograft procedure. Patients treated less well, or later, with cysteamine
therapy, displayed renal function results that were intermediate between those of well-treated patients and
those of patients not treated with cysteamine. Well-treated patients grew at approximately a normal rate,
approaching the fifth percentile curve for normal children and growing parallel to it. These studies were
done with earlier forms of cysteamine (cysteamine hydrochloride, and phosphocysteamine). The form of
cysteamine approved by the FDA (cysteamine bitartrate, Cystagon) has led to lower mean levels of
leukocyte free-cystine, 272 presumably because of improved patient compliance. Most cystinosis patients
who are compliant with Cystagon maintain their leukocyte free-cystine level below 1 nmol half-cystine per
mg protein. One patient with intestinal dysmotility received intravenous cysteamine, with leukocyte cystine
depletion similar to that achieved by equivalent oral doses of cysteamine. 273
Relationship between creatinine clearance and age in nephropathic cystinosis. The thin line represents
the normal increase in renal function for the first three years of life as the kidney grows, followed by a very
slow decline in clearance. The triangles represent the natural history of renal deterioration in cystinosis,
with end-stage renal disease predicted at 10 years of age. The squares give values for partially treated
patients, and th...
Other promising results have come from measurements of parenchymal cell cystine concentrations in
patients treated for several years with oral cysteamine. 90 In particular, the mean muscle cystine content
for 15 patients treated for 4 to 11 years with cysteamine therapy was one-eighth the mean value for 11
patients the same age but not treated with cysteamine. Moreover, a single 9-year-old boy treated from
age 1 with oral cysteamine had cystine values in his kidney, liver, lung, and pancreas that were fifty- to
one hundredfold less than those of an age-matched cystinosis patient who never received cysteamine.
The treated patient also had no crystals in his liver. Cysteamine has been reported to protect against the
cystinosis encephalopathy, 274 and one study demonstrated that proper oral cysteamine therapy obviates
the requirement for thyroid replacement in cystinosis patients. 254 The combined findings of parenchymal
organ cystine depletion, functional improvement in growth and glomerular filtration rate, and prevention of
hypothyroidism provide powerful evidence for the efficacy of systemic cysteamine therapy as the
treatment of choice for nephropathic cystinosis. The value of early diagnosis cannot be overemphasized,
because intervention with cysteamine in the first 2 years of life can allow for critical growth in absolute
renal function. In addition, the functional benefit to nonrenal organs indicates that oral cysteamine should
be offered to posttransplant as well as pretransplant patients.
The importance of frequent monitoring of the leukocyte free-cystine level was demonstrated when van’t
Hoff and Gretz studied patients in the U.K. and Ireland at a time when such monitoring was not the
standard. 275 Their patients were receiving significantly less cysteamine, and apparently deriving less
benefit from this therapy compared with patients in the United States and Canada. Their leukocyte
free-cystine values were also higher. This study led to a more aggressive management of cystinosis in the
U.K. and Ireland, with more frequent leukocyte cystine measurements. The optimal frequency of cystine
dosage remains controversial. Following oral administration of cysteamine, plasma levels peak in
approximately 2 h, with a rapid fall to very low levels by 6 h. 272 Consequently, the authors of this chapter
urge their patients to take the drug as close to every 6 h as possible. The 20 years of clinical experience
that demonstrated cysteamine’s effectiveness were based on patients receiving medication every 6 h.
Before changing to a different schedule, there should be convincing evidence that the new schedule
results in leukocyte cystine depletion to levels below 1 nmol half-cystine/mg protein at the end of the
longest period between doses.
Cysteamine has served as a duodenal ulcerogenic in rats, 276 and it depletes somatostatin 277, 278 and
pituitary prolactin 279, 280 in rats given doses much larger than those used in humans. (Blood levels of
cysteamine in treated cystinosis children reach only 30 to 80 µM 1 h after a dose. 281, 282 ) Chronic
cysteamine administered intraperitoneally to mice has not altered hepatic microsomal aryl hydrocarbon
hydroxylase activity compared with controls. 283 Standard treatment of patients with cysteamine has
revealed inhibition of glycine turnover, 284 blunting of a prolactin response in thyrotropin-releasing
hormone, 285 and conversion of apolipoprotein E 3 to an apolipoprotein E 4 phenotype on isoelectric
focusing, 286 but no clinical ramifications have accompanied these laboratory findings. The hepatic
veno-occlusive disease that is reportedly due to cysteamine therapy 287 appears more likely to be a
complication of cystinosis itself. 288 Hepatomegaly is no more frequent among patients treated with
cysteamine than among those who never received cysteamine. 191
Because of family history, some patients are diagnosed shortly after birth and started on cysteamine at a
very early age. Such patients have done extremely well, but in most cases, still developed the renal
Fanconi syndrome. 289, 290 In addition, older patients treated chronically with oral cysteamine have
exhibited no improvement in their renal tubular Fanconi syndrome. 176 The reason why cysteamine is so
successful in protecting glomerular, but not tubular, function is not understood.
We have noted that both males and females treated with cysteamine from early childhood progress
through puberty in a normal fashion. Moreover, several women with cystinosis and a renal allograft have
had successful pregnancies, including one in which placental crystals were documented. 80 To our
knowledge, none of these women was receiving significant doses of cysteamine. Recent studies of
developmental toxicity of phosphocysteamine in the rat are of concern. 291, 292 Pregnant rats were given 1
dose per day of phosphocysteamine from days 6.5 to 18.5 postconception, and fetuses were examined at
day 20.5. No apparent developmental toxicity was observed in fetuses receiving doses up to 75 mg
cysteamine/kg/day, but at doses of 100 mg, and especially 150 mg, cysteamine/kg/day, fetuses
demonstrated cleft palate and kyphosis, as well as intrauterine growth retardation and fetal death. 292 It is
difficult to know whether a woman receiving cysteamine would be subject to a similar risk for her fetus. A
hypothetical adult woman with cystinosis (60 in, 110 lbs, 1.46 m 2 body surface area) taking 1.3 g/m 2 /day
of cysteamine would be receiving approximately 38 mg/kg/day of cysteamine.
Recently, cysteamine was demonstrated to inhibit proliferation of neural neoplastic cell lines 293 and
replication of human immunodeficiency virus type I, 294 and to have potential as a contraceptive anti-HIV
agent. 122
Cysteamine Eyedrops.
Despite years of oral cysteamine therapy, children with cystinosis continued to accumulate corneal
crystals, causing painful erosions and ulcerations in older patients. One 12-year-old boy had such
debilitating corneal pain that he underwent a penetrating keratoplasty, 196 with marked improvement in his
quality of life. The epithelial cells of his cornea were cultured, and exhibited both cystine storage and
susceptibility to depletion by cysteamine. 295 This meant that cystinotic corneal cells were intrinsically
capable of responding to cysteamine therapy, and that low cysteamine concentrations in the avascular
cornea were most likely responsible for the failure of oral cysteamine to lower the corneal crystal content.
Delivery might be readily achieved using topically administered cysteamine.
After demonstrating the safety of cysteamine eyedrops in rabbit eyes, 295 two cystinosis patients under
age 2 years were enrolled in a randomized, double-blind clinical trial involving a placebo (normal saline)
for one eye and 10 mM (0.1 percent) cysteamine plus normal saline for the other eye. 295 Eyedrops were
administered every hour while awake, with a marked diminution in corneal crystals in the treated eyes
after 4 to 5 months of therapy. By 1990, 29 patients up to 31 years of age had entered the
double-masked, randomized, placebo-controlled protocol, which then employed 50 mM (0.5%)
cysteamine in normal saline. Eight of 18 patients under 42 months of age, and 2 of 11 patients 4 to 31
years of age, showed marked clearing in one eye, which was subsequently shown to be the
cysteamine-treated eye. 296 After breaking the randomization code, both eyes were treated with
cysteamine eyedrops. Currently, over 100 patients are under protocol, and there have been no side
effects attributable to this therapy. The formulation now contains preservative and is stored frozen before
use. A formulation that is stable at room temperature is being investigated. At present, the U.S. Food and
Drug Administration has not approved any formulation of cysteamine eyedrops. Other centers have also
been successful in clearing corneal cystine crystals with cysteamine eye drops. 297, 298
Some generalizations can be drawn concerning the use of cysteamine eyedrops. First, compliance
determines the outcome. When drops are given 10 to 14 times per day, a marked decrease in crystal
density is apparent within 4 to 8 months. If given less frequently, 299 such as 3 to 4 times per day, 300 no
benefit is evident. Second, young patients with fewer crystals (Fig. 199-8A and B) respond better and
faster than older ones with packed corneas. Several children are now approximately 6 years old with no
crystals visible in their corneas. Older patients can lose the haziness to their corneas (Fig. 199-8C and D)
and can experience improved visual acuity. Third, crystal formation appears to be a reversible process.
Crystals can be removed at any age, and stopping therapy or reducing the frequency of administration
(e.g., to every 4 h) results in recurrence of corneal crystals. Fourth, because the concentration of
cysteamine has not been pushed to toxicity, the optimal concentration has not yet been determined.
Finally, virtually all compliant patients experience relief of their photophobia.
Photographs of corneal cystine crystals before and after cysteamine eyedrop therapy in cystinosis
patients. A, Right eye of a 28-month-old boy before topical cysteamine therapy, showing abundant
crystals. B, Same eye as in A after 7 months of 0.5% cysteamine eyedrops administered 8 to 12 times per
day, with clearing of corneal crystals. C, Left eye of 21-year-old woman prior to cysteamine eyedrop
therapy. Uniform haziness typifies app...
Use of Growth Hormone

The use of cysteamine/phosphocysteamine has markedly improved the growth of cystinosis
patients. 176, 254 After starting therapy, patients tend to have a normal growth rate, but do not exhibit
“catch-up” growth. Thus, most patients remain below the third percentile for height. There is some
evidence that indomethacin also has a positive influence on growth (see reference 249 and “Symptomatic
Therapy” above). The long-term efficacy of recombinant human growth hormone (rhGH) for short stature
in patients with chronic renal disease is established. 301 Several patients with cystinosis have received
rhGH because of its salutary effect on short stature, even in the absence of growth hormone
deficiency. 302–306 In 1993, a controversy developed as to whether the increase in muscle mass in
cystinosis patients who are treated with rhGH might lead to the earlier need for renal
transplantation. 305, 307, 308 All investigators involved in this debate agreed that further studies were
required to answer this question. The European Study Group on Growth Hormone Treatment for Short
Children with Nephropathic Cystinosis has completed a study on 36 cystinosis patients. It found an
excellent increase in growth velocity (greater than twofold), and no acceleration of the decline in renal
function. 309 Their study also provided further evidence that cysteamine therapy reduces the progression
of renal failure in cystinosis.
Family Support Group

The Cystinosis Foundation 310 has been active since 1983 in supporting families, physicians, and
investigators involved in cystinosis.
CYSTINOSIS VARIANTS
There are two basic cystinosis phenotypes: nephropathic and nonnephropathic. The nephropathic form
can be further subdivided, based on age of presentation, as shown in Table 199-3. Each type appears to
represent a different, but allelic, mutation, and there likely exists a continuum of disease severity.
Table 199-3: Different Forms of CystinosisSeparate Window
Nephrophatic Nonnephropathic
Infantile (6–18 months) Ocular (formerly adult or benign)
Late-onset
Child (4–5 years)
Adolescent (12–15 years)
Adult-onset (26 years)
The infantile nephropathic form, described above, is the most common and devastating variant of
cystinosis, with presentation in the first year or two of life. In the late-onset forms of nephropathic
cystinosis, the age of presentation ranges from 2 to 26 years. 311–321 Age of onset and symptoms are
usually similar in affected siblings or in members of a family. The most usual age of presentation has been
12 to 15 years. 318 These patients have crystalline deposits in the cornea and conjunctiva, and have
cystine crystals within bone marrow aspirates. Patients with late-onset cystinosis often do not develop the
complete Fanconi syndrome, but their renal disease may progress to end-stage renal failure within a few
years of diagnosis. In one family, two sisters were found to have proteinuria during a routine medical
examination at 25 years of age. 322 The older sister had rapid deterioration of glomerular function and
required a renal transplant at 30 years of age. No specific diagnosis was made at that time. The younger
sister had a similar course, also requiring a transplant at 30 years of age. However, the younger sister had
a renal biopsy at age 26 that demonstrated cystine crystals. Both patients have late-onset cystinosis, and
they exhibit compound heterozygosity for apparently mild mutations in CTNS. 144
Other patients have a benign, ocular, or nonnephropathic form of cystinosis that is usually discovered by
serendipity when an ophthalmologic examination reveals crystalline opacities within the cornea and
conjunctiva. This was first reported in 1957, 323 and since then, many more cases have been
reported. 324–333 These patients may suffer from photophobia similar to that of patients with the
nephropathic forms of cystinosis, but their photophobia may not begin until middle age, and is usually not
debilitating. Because the only patients found to have this condition are those who have had a slit-lamp
examination, it is possible that many individuals with this form of cystinosis have no eye symptomatology
and are never diagnosed. Patients with ocular cystinosis have crystalline deposits in their bone marrow
and elevated leukocyte cystine levels, but never have renal disease. They appear to have a normal life
expectancy, but because some patients with late-onset cystinosis do not develop renal dysfunction until
their mid-twenties, patients with presumably ocular cystinosis must be followed diligently.
Patients with ocular cystinosis do not appear to accumulate cystine crystals in their kidneys, 325, 329 which
may explain their lack of kidney pathology. They also do not develop retinopathy. Patients with ocular
cystinosis tend to have lower levels of leukocyte cystine than do patients with late-onset cystinosis, who,
in turn, have lower levels of leukocyte cystine than do patients with infantile nephropathic
cystinosis. 311, 326 However, there is much overlap among these values and the measurements were
performed using mixed leukocyte preparations, without regard for the fact that the cystine is stored
primarily in polymorphonuclear leukocytes. 85, 241
Lysosomes from a patient with late-onset cystinosis exhibited deficient cystine transporting ability. One
patient with benign/ocular cystinosis had 9 percent and 29 percent residual lysosomal cystine transporting
capacity in two different experiments. 332 This patient has well-defined mutations in CTNS. 144a The
transport experiments were also performed with lysosomes from different patients with late-onset and
benign cystinosis by a different laboratory with similar results. 334 Thus, it appears that the transport defect
is most severe in infantile nephropathic cystinosis and least severe in ocular cystinosis.
Future Research
The major goals of further investigations into cystinosis are to improve treatment, to understand the
pathophysiology of the disease, and to expand our knowledge of the cellular mechanisms involved in
lysosomal cystine transport.
To improve the clinical care of cystinosis, we must diagnose the disorder earlier by fostering a greater
level of suspicion. To prevent extrarenal complications, we should consider treating all cystinosis patients
with oral cysteamine. To prevent progressive nephrocalcinosis, we should reduce to a minimum the
amount of phosphate supplements we provide our adult, pretransplant patients. To determine how well
oral cysteamine depletes cystine from the central nervous system, we should use animal models arising
from CTNS gene manipulation.
We do not yet understand how cystine accumulation causes clinical disease. Does it destroy cells, such
as those in the renal tubules, or merely impair their function? Is it soluble or crystalline cystine that does
the damage? How can ocular cystinosis patients store crystalline amounts of cystine in their corneas, and
never have renal disease? These questions can be addressed with several available tools. First, renal
tubular cells have been cultured from cystinosis patients so that the progression of tubular damage can be
studied in vitro. 335 Second, whole animals, isolated tubules, 336 and cultured tubular cells can be loaded
with cystine dimethylester to simulate the cystinosis condition. In addition, the cloning of CTNS means that
transgenic mice can be created to investigate the cause of organ and tissue damage. Mice with ocular or
intermediate cystinosis will be of particular interest to determine why some tissues are more or less
severely affected than others. Expression studies in mammalian or insect cells can also reveal the
molecular basis for milder disease in some patients. Looking further into the future, CTNS gene therapy
for corneal cystine accumulation may serve as an adjunct to oral cysteamine therapy, if vectors can be
targeted to stromal keratinocytes.
Regarding lysosomal cystine transport, expression and proteoliposome reconstitution studies can vastly
improve our knowledge of the kinetics and structure-function characteristics of the CTNS protein.
Antibodies can be used to follow the CTNS protein from synthesis through processing to incorporation into
the lysosomal membrane. These findings pertain directly to the hitherto unknown mechanism of
intracellular protein sorting and trafficking. Finally, the lysosomal leader sequence of CTNS can be
exploited to identify other lysosomal membrane transport genes, including that responsible for transport of
cobalamin (see reference 337 and Chap. 155).
DOI Reference Number: http://dx.doi.org/10.1036/ommbid.233
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Part 21: Membrane Transport Disorders Chapter 199: Cystinosis: A Disorder of Lysosomal Membrane Transport

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Part 21: Membrane Transport Disorders Chapter 199: Cystinosis: A Disorder of Lysosomal Membrane Transport

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What is cystinosis and what causes it?

What is cystinosis and what causes it?

What are the main clinical manifestations of cystinosis?

What are the main clinical manifestations of cystinosis?

Chapter 199: Cystinosis: A Disorder of Lysosomal Membrane Transport

PART 21: MEMBRANE TRANSPORT DISORDERS

Chapter 199: Cystinosis: A Disorder of Lysosomal Membrane Transport

infants. Heterozygotes for all types of cystinosis are clinically normal.

Cystine Storage in Cystinosis

Table 199-1: Cystine Content of Cystinotic Tissue and Cells

Kidney 1 25.6 – 156

1 – 19.8, 21.0 – 339

Brain 2 – 0.02–0.08 1 0.17 – 87

Lung 1 44.5 – 156

Pancreas 1 35.8 156

1 – 34.5, 42.4 – 339

Gallbladder 1 2.1 – – 156

3 – 6.9–10.0 2 – <0.1 311

6 – 6.7–14.3 3 – <0.1 311

Cultured leukocytes 3 – 0.31–3.10 3 – <0.03 341

Lysosomal Cystine Transport

Mechanism of Cystine Depletion by Cysteamine

Source of Lysosomal Cystine in Cystinosis

Table 199-2: CTNS Mutations and Frequencies

CTNS Domain Mutation # of Alleles *

Exons 1–10 57-kb del 143 †

Leader sequence 357delGACT 12

Transmembrane regions 753G → A 27

Nontransmembrane regions 479 + 1G 1

CLINICAL FEATURES AND PATHOLOGY

Presentation and General Course (Fig. 199-5)

Renal Tubular Involvement

Other Ocular Tissues.

Nervous System Involvement

Hepatic and Gastrointestinal Complications

Other Clinical and Laboratory Abnormalities

Cystinosis as an Adult Disease

Specific Treatment to Reduce Cystine Storage

Oral Cysteamine Therapy.

Use of Growth Hormone

Family Support Group

Table 199-3: Different Forms of CystinosisSeparate Window

Infantile (6–18 months) Ocular (formerly adult or benign)

Child (4–5 years)

Adolescent (12–15 years)

Adult-onset (26 years)

DOI Reference Number: http://dx.doi.org/10.1036/ommbid.233

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147. Markello TC: Unpublished data.

156. Gahl WA: unpublished data.

197. Kaiser-Kupfer Muriel I, Gahl WA: Unpublished data.

212. Charnas LR, Dalakas M: Unpublished data.

229. Ishak K: Personal communication, March 9, 1992.

238. Fox PC, Baum BJ, Gahl WA: Unpublished data.

242. For details on leukocyte preparation, seehttp://medicine.ucsd.edu/cystinosis.

310. 2516 Stockbridge Drive, Oakland, CA 94611.http://cystinosisfoundation.ucsd.edu.

334. Greene AA, Schneider JA: Unpublished data.

340. Thoene JG , unpublished data.