Nephropathic Cystinosis
mutation is a 57,257bp deletion associated in the homozygous or heterozygous state with the classic disease phenotype in about 76% of patients of European origin, and shown to be due to a founder effect.10,11
confirming that the different subtypes are allelic; the nephropathic forms are often due to mutations affecting conserved amino acids associated with transmembrane regions of the protein.11
Smaller
deletions and missense and frameshift mutations have been described. In severe cases, mutant CTNS alleles are predicted to produce truncated cystinosin, while mild cases have cystinosin with some residual activity12
and diminished cystine accumulation.7 Tissue-
specific splicing factors may allow for variable use of mutant splice acceptor sites in, for example, the kidney.13
Although several investigations support a genotype–phenotype correlation, the true role of factors such as environment, modifying genes, pro-apoptotic genes,14
tissue-specific splicing factors and
subcellular co-localisation in producing the cystinosis phenotype has not been delineated.
Clinical Characteristics of Pre-transplant Patients
Typically, cystinosis patients present at six to 12 months of age with failure to grow and symptoms of renal tubular Fanconi syndrome.15 Some children present as toddlers with short stature, muscle weakness and renal tubular wasting. In fact, NC is the most common identifiable cause of renal Fanconi syndrome in children. Clinical manifestations include polyuria; losses of electrolytes; generalised aminoaciduria with normal plasma levels of amino acids; proteinuria; glycosuria; carnitinuria; dehydration; metabolic acidosis accompanied by anorexia and vomiting; hypophosphataemic, vitamin D-resistant rickets with osteomalacia;
hypocalcaemia with tetany; and
hypokalaemia with possible cardiac complications. At the time of diagnosis, the height of many patients is below the fifth percentile.16 The growth retardation and failure to thrive are at least partially due to renal electrolyte, calcium and phosphate losses. Rickets and renal osteodystrophy contribute to the skeletal deformities of cystinosis; chronic renal failure and direct deposits of cystine crystals in the bone combine to impair growth.17
Progressive decline of glomerular filtration is the clinical hallmark of NC.
The cause of the renal tubular Fanconi syndrome in cystinosis remains unknown, but cystine storage in proximal tubular cells decreases adenosine triphosphate (ATP) levels and reduces sodium- coupled transport of electrolytes into these cells.11
Observations in
CTNS knockout mice suggest that the proximal tubulopathy is secondary to a metabolic effect rather than cystine storage per se.8 Phosphate depletion and dissipation of the sodium gradient may be involved in the initial development of Fanconi syndrome.18
After the initial diagnosis of cystinosis, both renal and non-renal involvement progresses. Hypercalciuria and hyperphosphaturia lead to medullary nephrocalcinosis.19,20
Photophobia, due to corneal crystal
deposits, is a distinct and universal feature of NC; crystals are always detected by 16 months of age.13
Thyroid function declines
progressively; atrophic thyroid glands exhibit cystine crystals, with destruction and infiltration of the epithelium.21,22
Patients with
cystinosis also have pituitary resistance to thyroid hormones, with increased serum thyroid-stimulating hormone (TSH).23 puberty is delayed in patients without cysteamine therapy.4
The onset of
56
NC accounts for about 5% of childhood renal failure,24 CTNS mutations account for all forms of cystinosis, which occurs
by 10 years of age in most untreated patients. Histological studies have revealed abundant crystals within macrophages of the kidney.25 Biopsies reveal fusion of foot processes, thickening of Bowman’s basement membrane and interstitial cells containing hexagonal crystals surrounded by a typical lysosomal membrane,26 glomerular obsolescence and interstitial fibrosis.26
leading to It is possible that
proximal tubular dysfunction causes a high sodium chloride concentration in the macula densa, activating a glomerular–tubular feedback mechanism and decreasing the glomerular filtration rate (GFR), resulting in glomerular failure.27,28
Early treatment with cystine-
depleting agents (see below) slows or stops this progressive glomerular damage and can postpone or prevent the need for renal transplantation.29
Together, successful renal transplantation and cysteamine therapy cure renal failure and prolong survival.30
Diagnosis
The diagnosis of cystinosis is often based on a high index of suspicion in patients with documented Fanconi syndrome, delayed height and weight, impaired renal function and GFR, abnormal thyroid function studies and the presence of crystals on slit-lamp examination of the cornea. The clinical diagnosis should be confirmed by measuring the cystine concentration of polymorphonuclear leukocytes, now best performed by mass spectrometry. Individuals with NC generally have 3.0–23.0 nanomoles of half-cystine per mg of leukocyte protein.31
On
biopsy of various tissues, cystine crystals appear hexagonal or rectangular, and are birefringent under polarising light.12
Targeted
molecular genetic testing for a panel of mutations, optimised for the French/Canadian population, is available on a clinical basis.12
Pre-
natal diagnosis involves measuring cystine levels in cultured amniocytes or samples of chorionic villi, and treatment can be initiated shortly after birth in affected individuals.32
Treatment
Symptomatic Therapy
Adequate intake of calories, fluids and electrolytes mitigates the metabolic disturbances caused by the Fanconi syndrome and chronic renal failure. Water replenishment, along with phosphate, potassium, calcium, magnesium and carnitine supplementation, are essential components of the treatment of cystinosis.15
Indomethacin therapy is
sometimes employed for polyuria. Nutritional support for protein- calorie malnutrition can be provided by specialised formulas and occasionally requires an oral, gastric or jejunal tube; parenteral nutrition is recommended in rare cases with severe dysphagia or gastrointestinal dysmotility. Care must be taken to maintain the mastication and swallowing processes. A cystine-free diet has not
proved to be effective and is not recommended. Prokinetic agents, H2 blockers and agents for dyspepsia can alleviate digestive and dysmotility problems. Recombinant human growth hormone (rhGH) appears safe and effective in promoting long-term growth in children with NC and should be started in the early pre-pubertal period;33
in
one study, growth rates increased by two- to four-fold during rhGH treatment.16
progression of chronic renal failure in children.33
Therapy with rhGH for up two years did not accelerate the Treatment of
hypothyroidism with oral L-thyroxine replacement greatly improves the quality of life of children with hypothyroidism.34
Vitamin D is
indicated for children with metabolic bone disease to enhance phosphate and calcium reabsorption; larger vitamin D doses may be required during the adolescent growth spurt. Angiotensin-converting enzyme (ACE) inhibitors are frequently prescribed to decrease
EUROPEAN NEPHROLOGY
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