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Cystinosis.pptx
- 1. S L I D E 0 Cystinosis Ibrahim Sandokji
- 2. S L I D E 1
- 3. S L I D E 2 Fanconi syndrome Growth failure Episodes of hypovolemia Persistent acidosis Chronic hypokalemia Rickets Hypophosphatemia Proteinuria Glucosuria
- 4. S L I D E 3 Genetic conditions associated with Fanconi syndrome Cystinosis Tyrosinemia Hereditary fructose intolerance Galactosemia Glycogen storage disease (type I) Wilson disease Lowe syndrome
- 5. S L I D E 4 ABP Content Specification
- 6. S L I D E 5 Pathogenesis
- 7. S L I D E 6 Cystinosis • Lysosomal storage disease characterized by an accumulation of cystine in different organs and tissues, leading to severe organ dysfunction. • Types: – Infantile (nephropathic) form (autosomal recessive) – Late-onset (juvenile) form – Adult (benign) form
- 8. S L I D E 7
- 9. S L I D E 8 Kidney Pathophysiology • The hallmark is accumulation of cystine crystals within proximal tubular cells (PTCs) • PTCs loose brush border -> flattened • Thick basement membrane • These tubular changes typically begin at the glomerulotubular junction and extend distally, evolving to tubular atrophy with development of characteristic swan neck deformities • In addition, heavy inflammatory cell infiltrates can be observed in the renal interstitium Cystine crystals accumulate within lysosomes
- 10. S L I D E 9
- 11. S L I D E 10 Epidemiology • It is the leading cause of inherited renal Fanconi syndrome in children (20% of cases of hereditary tubular disorders). • Nephropathic cystinosis affects 1 of every 100,000 to 200,000 children • Higher incidence in some regions in France and Quebec in Canada
- 12. S L I D E 11 Genetics of Cystinosis • More than 100 different mutations have been identified in the CTNS gene (Large deletions, missense mutations or in-frame deletions). • 57-kb deletion -> complete loss of cystinosin. ~50% of cystinosis cases in people of European descent. • 65-kb deletion -> one-third of patients with cystinosis • Mutations that change very small regions of the CTNS gene may allow the transporter protein to retain some of its usual activity, resulting in a milder form of cystinosis.
- 13. S L I D E 12 Clinical Features • Normal at birth • 6–9 months -> Failure to thrive • 6–18 months -> kidney dysfunction; polyuria and polydipsia, and vitamin D-resistant rickets • Renal insufficiency by ~10 years of age if untreated (and at ~20 years of age if cysteamine treatment is initiated before 5 years of age) • Deposition of cystine crystals in the cornea occurs early in the course of disease, causing photophobia and painful corneal erosions. • Second to third decade of life -> hypothyroidism, hypogonadism, diabetes, myopathy, and deterioration of the central nervous system
- 14. S L I D E 13 Clinical Features
- 15. S L I D E 14 Diagnosis • Elevated leukocyte cystine level • Cystine corneal crystals by slit lamp examination • CNTS gene mutation
- 16. S L I D E 15 Treatment • Current therapies – Supportive therapy – Cysteamine – Renal transplant • Future direction: – Haematopoietic stem cell transplantation with gene therapy
- 17. S L I D E 16 Supportive Therapy • Water intake • Sodium and potassium bicarbonate supplements • Phosphate and vitamin-D • Thyroxine and Growth hormone • Feeding problems (enteral vs parenteral)
- 18. S L I D E 17 Cysteamine • It enters the cell -> concentrates within the lysosomes -> reacts with cystine to form cysteine-cysteamine complex -> able to leave the lysosomes. • It should be started as soon as the diagnosis of cystinosis is confirmed • It preserves renal function, prevents hypothyroidism, and improves growth in affected children • It has no effect on established renal Fanconi syndrome.
- 19. S L I D E 18
- 20. S L I D E 19
- 21. S L I D E 20
- 22. S L I D E 21 Renal transplantation
- 23. S L I D E 22 • Cystine-induced tubular dysfunction does not recur on the graft
- 24. S L I D E 23 Other types of cystinosis • Late-onset (juvenile) cystinosis – Presents around eight years of age with manifestations due to renal tubular dysfunction – Progressive decline in GFR, resulting in ESRD by 15 years of age • Adult cystinosis – The most benign form – Patients are generally asymptomatic except for photophobia or ocular discomfort due to crystal deposition in their cornea
- 25. S L I D E 24 Summary • Cystinosis is an autosomal recessive lysosomal storage disease caused by a defect in the lysosomal cystine transporter, cystinosin, which results in an accumulation of cystine in all organs • Renal Fanconi syndrome often precedes extrarenal manifestations • Early recognition and therapy with cysteamine is important to prevent many long term complications including ESRD • In patients who develop ESRD, renal transplantation is the preferred therapy, as outcome is excellent
- 26. S L I D E 25 Thank you!
Editor's Notes
- Lysosomes are membrane-enclosed organelles that contain an array of enzymes capable of breaking down all types of biological polymers—proteins, nucleic acids, carbohydrates, and lipids. Lysosomes function as the digestive system of the cell, serving both to degrade material taken up from outside the cell and to digest obsolete components of the cell itself.
- Physiopathology of cystinosis. Cystinosis is a monogenic hereditary disease caused by mutations or deletions in the ubiquitous gene CTNS. This gene encodes a seven-transmembrane lysosomal protein, which is a proton-driven cystine transporter. However, the physiopathology of cystinosis suggests that cystinosin has other functions and/or other genes influence the pace and extent of the disease. This could explain the high variability in age of the appearance and severity of the complications observed in patients taking cysteamine, which allows cystine to exit the lysosomes. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate. Normally Cystine is derived from protein degradation within the lysosomes of cells. Free cystine is normally transported through the lysosomal membrane to the cytosol where it is reutilized after its transformation to cysteine. In cystinosis, cystine accumulates inside the lysosomes because of a defect in the gene that encodes cystinosin, the protein that transports cystine across the lysosomal membrane. Cystine is poorly soluble and forms crystals as its concentration increases.
- Cytogenetic Location: 17p13.2, which is the short (p) arm of chromosome 17 at position 13.2
- Sodium wasting and severe urinary concentrating defect result in polyuria (reaching 2 to 3 L/day), polydipsia, poor weight gain, growth retardation, vomiting, constipation, weakness, unexplained fever, and acute dehydration episodes. Excessive losses of potassium, sodium, and bicarbonate lead to hypokalemia, hyponatremia, and metabolic acidosis. Vitamin D-resistant rickets (manifested by swelling of the wrists, frontal bossing, and genu valgum) is often noted at presentation due to phosphate wasting and hypophosphatemia.
- Nonrenal findings include ocular abnormalities, hepatomegaly, hypothyroidism, muscle weakness, and growth retardation.
- Cysteamine therapy before five years of age significantly decreased the incidence and delayed the onset of ESRD, and delayed the onset of hypothyroidism, diabetes, and neuromuscular disorders. In addition, the life expectancy was significantly improved in cysteamine-treated versus untreated patients