Diseases of the microfibril/elastic fiber system Juan Pablo Olano M.D. Associate Professor Director, Residency Training Program Member, Center for Biodefense and Emerging Infectious Diseases UTMB, 2010 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. Microfibril (non-fibrillin) associated proteins MAGP-1 MAGP-2 MFAP3-4 AAAP-40 Fibulin BMP Proteoglycans (perlecan, decorin, versican) 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) 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 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). 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. 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 exonsChromosome 15q21 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. 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 Genetics TGFβR1 and 2 are associated with severe vascular manifestations • Aneurysms at early age and distant aneurysms Other related disorders MASS phenotype and familial mitral valve prolapse: Myopia, minimal aortic dilation, subtle skeletal changes, skin stria. Familial tall stature Contractural arachnodactyly 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 Clinical manifestations (cont) Skeletal system • Pectus excavatum/carinatum • Hypermobility • Scoliosis • Reduced upper/lower extremity ratios • Pes planus • Long tapering fingers and toes • Dolichocephaly Clinical manifestations (cont) Ocular • Ectopia lentis • Flat cornea • Hypoplastic iris • Increased axial length of ocular globe Clinical manifestations (cont) Integumentary system: • Skin striae. • Hernias Marfan Syndrome. Hemopericardium Marfan Syndrome. Aortic tear Marfan Syndrome. Aortic tear Marfan Syndrome. Aortic dissection Marfan Syndrome. “Floppy” Mitral Valve Thanks for your attention