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Diseases of the microfibril /elastic fiber system

Diseases of the microfibril /elastic fiber system. Juan Pablo Olano M.D. Professor UTMB , 2013. Microfibril/elastic fiber system. Extracellular matrix of every organ Abundant in organs subject to mechanical stress

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Diseases of the microfibril /elastic fiber system

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  1. Diseases of the microfibril/elastic fiber system Juan Pablo Olano M.D. Professor UTMB, 2013

  2. Microfibril/elastic fiber system • Extracellular matrix of every organ • Abundant in organs subject to mechanical stress • Elastin: Core protein. Fibrillin directs deposition of tropoelastin during development • Microfibrils: Unbranching chains sheathing the elastin core. Fibrillin 1 and 2. Fibrillin 3 recently described. 2 and 3 preferentially expressed in embryonic development. • Microfibrils can be present without elastin • Biomechanical anchors in basement membranes and areas of repeated mechanical stress.

  3. Microfibril (non-fibrillin) associated proteins • MAGP-1 • MAGP-2 • MFAP3-4 • AAAP-40 • Fibulin • BMP • Proteoglycans (perlecan, decorin, versican)

  4. Genetic disorders of the elastic fiber system • Elastin gene • Supravalvular aortic stenosis • Autosomal dominant cutis laxa • FBN1, TGFβR1 and TGFβ2: • Marfan’s syndrome and related disorders: • Neonatal Marfan syndrome • Isolated ectopia lentis • Loeys-Dietz syndrome • Familial and non-syndromic thoracic aortic aneurysms and dissections. • Shprintzen-Goldberg craniosynostosis syndrome • Weill-Marchesani syndrome • FBN2 • Congenital contractural arachnodactyly (Beals syndrome)

  5. Fibrillin 1 • Multi-domain protein • EGF-like motif with a conserved calcium binding sequence. • Latent TGFβ binding protein motif. • Fib motif • Mutations present in all three domains. • nMFS associated with mutations in exons 24-32. • No other correlations exist

  6. TGF-β • Cell proliferation, differentiation • Apoptosis • ECM formation • TGF-β1 abundant in ECM. Cysteine rich. • Secreted as homodimeric proprotein • Dimeric propeptide or Latency associated polypeptide (LAP) and growth factor • LAP is bound to Latent TGF β binding proteins (LTBP) forming large latent complex or LLC • LTBP play an important role in folding, secreting and targeting TGF β in ECM. Also cysteine rich. • LTBP-1 interacts with fibrillin-1 (stabilizer).

  7. Marfan’s syndrome • Autosomal dominant inherited disease that affects the microfibril/elastic fiber system and involves several organ systems including the heart, aorta, skeleton and the eye. Clinical presentation is extremely pleiotropic. • Incidence: 2-3/10,000 population • Mutations • 1/3: Shortened molecules and decay • 2/3: Binding domains: Protein-protein interations, calcium binding domains.

  8. Genetics • 1991: Mutations in FBN1. High penetrance. • 25% of cases are the index case: New mutations in the egg or sperm of parents. • >600 mutations described (most missense). • Fibrillin: 350 kDa glycoprotein. 230 kb. 65 exons. Chromosome 15q21

  9. Genetics • MFS type 2 (MFS locus 2): • TGFβR1 and TGFβR2 • Described in 1993 in a French cohort • Caused by TGFβR2 • Cardiovascular and skeletal findings. Not ocular. • Difficult to differentiate from Loeys-Dietz syndrome • Loeys-Dietz syndrome • Described in 2005 • Aortic aneurysms, hypertelorism, bifid uvula, cleft palate, arterial tortuosity. • TGFβR1 and 2.

  10. Genetics • Familial thoracic aortic aneurysms and dissections • Described in 2005 • FBN1, TGFβR1 and 2. • Overlap with Loeys-Dietz syndrome (arterial tortuosity). • Shprintzen-Goldberg syndrome • Craniosynostosis, marfanoid skeletal abnormalities and developmental delay. • FBN1 and TGFβR1

  11. Genetics • TGFβR1 and 2 are associated with severe vascular manifestations • Aneurysms at early age and distant aneurysms

  12. Other related disorders • MASS phenotype and familial mitral valve prolapse: Myopia, minimal aortic dilation, subtle skeletal changes, skin stria. • Familial tall stature • Contractural arachnodactyly

  13. Marfan Syndrome:Clinical manifestations • Cardiovascular • Dilation of ascending aorta • Dissection of aorta (30-45% deaths in Marfan’s syndrome). • Mitral valve prolapse (more frequent than aortic lesions). • Dilation of pulmonary artery • Pulmonary system: • Blebs, spontaneous pneumothorax

  14. Clinical manifestations (cont) • Skeletal system • Pectus excavatum/carinatum • Hypermobility • Scoliosis • Reduced upper/lower extremity ratios • Pes planus • Long tapering fingers and toes • Dolichocephaly

  15. Clinical manifestations (cont) • Ocular • Ectopia lentis • Flat cornea • Hypoplastic iris • Increased axial length of ocular globe

  16. Clinical manifestations (cont) • Integumentary system: • Skin striae. • Hernias

  17. Marfan Syndrome. Hemopericardium

  18. Marfan Syndrome. Aortic tear

  19. Marfan Syndrome. Aortic tear

  20. Marfan Syndrome. Aortic dissection

  21. Marfan Syndrome. “Floppy” Mitral Valve

  22. Thanks for your attention

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