Marfan syndrome

From Iusmgenetics

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*Flo Hyman
*Flo Hyman
**Died of aortic rupture in the middle of a volleyball match.
**Died of aortic rupture in the middle of a volleyball match.
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http://media.photobucket.com/image/flo%20hyman/cougarcards/1977‐79SportscasterFloHyman12.jpg
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===Mode of inheritance===
===Mode of inheritance===
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*Aortic Diliatation
*Aortic Diliatation
**Enlargement
**Enlargement
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*http://www.avnrt.com/gigs/marfan1.gif
 
**Regurgitation
**Regurgitation
**Aneurysm
**Aneurysm

Current revision as of 13:22, 13 December 2011

Contents

[edit] Marfan syndrome

[edit] General background information

  • 1 of 10k-20k
  • 1 in 5,000 **10,000 live births
  • Flo Hyman
    • Died of aortic rupture in the middle of a volleyball match.

flo_hyman.jpg

[edit] Mode of inheritance

  • Autosomal Dominant Inheritance
    • Because of dominant-negative effect (impaired microfibril formation)
  • 75% are inherited
  • 25% de novo mutations
  • No Documented Cases of Non‐Penetrance
  • Many different missense mutations have been observed (allelic heterogeneity).
  • At least one known splicing mutation: IVS63+373 mutation creates an intronic GT sequence as a new acceptor site at the 5’ terminus and results in generation of a pseudoexon.
    • This resulted in a 93bp insertion between 8,379 & 8,380 (junction between exons 63 & 64)

[edit] Single important gene

  • 15q21.1: FBN1 gene codes for Fibrillin‐1
    • A major piece of the ECM
  • Fibrillin is present in the suspensory ligament, eleastic connective tissue (aorta & ligaments) and periosteum
  • 320 kDa glycoprotein, 2,871 AA
  • Has 3 types of repeating modules
  • Epidermal Growth Factor (EGF) like module
    • Occurs 47 times, 43 are Calcium binding EGF like modules
    • Each has 6 cysteine residues
  • TGF‐Beta Binding Protein (TGFBP) like module
    • Occurs 7 times
    • Each has 8 cysteine residues that form 4 disulfide bonds
  • Hybrid Module
    • Occurs twice

[edit] Etiology

  • Ca2+ binding fails in EGF-like domain mutations
    • Most common domain in the protein
    • Ca2+ binding required for protein‐protein interactions
    • Causes haploinsufficiency because half the proteins can't bind and binding between two functional proteins is required for function.


  • TGF‐β Binding Protein motif mutations
    • TGF‐β is important for ECM remodelling, matrix deposition, and MMP regulation.
    • FBN1 normally uses it's TGF‐β binding domains to sequester TGF‐β.
    • When the domain is mutated, TGF‐β is not sequestered and is therefore elevated.



  • Most mutations lead to less than 35% of the expected amount of fibrillin.

[edit] Pathogenesis

  • Happloinsufficiency with dominant-negative effect.
    • Both explain the pleiotrophy.

[edit] Phenotypic information

  • A pleotropic disease: affects several systems (skeletal, ocular, and cardiovascular).
  • NB: phenotype gets worse with age.

[edit] Ocular Abnormalities

[edit] Cardiovascular Abnormalites

  • Mitral valve prolapse
    • Regurgitation
  • Aortic Diliatation
    • Enlargement
    • Regurgitation
    • Aneurysm
  • marfan1.gif

[edit] Skeletal Abnormalities

[edit] Diagnosis

  • Typically diagnosed "clinically"
  • Ghent criteria: Major findings in 2 systems (3 systems w/out family history) and a minor feature in a 3rd
  • Systems
    • Ocular
    • Skeletal
    • Cardiovascular
  • MFS Genetic Test
    • bidirectional sequence analysis of 65 exons & splice sites in the FBN1 gene
    • Does not detect mutations in introns or large deletions
    • 99.9% accurate at detecting mutations in the 65 exons & splice sites
    • 70‐90% Sensitive
    • Won’t find mutation ~ 10% who meet Ghent criteria
    • Cost: $1800

[edit] Treatment

  • Use multidisciplinary management
  • Ocular: Ophthalmic lens correction for myopia, monitor for glaucoma & retinal detachment. Ectopic lens may need surgical intervention
  • Cardiovascular: monitor mitral valves and aorta through echocardiography; β blockers
  • Counseling: Advise against isometric exercises and impact sports. Pregnancy & aorta dilatation.
  • Life expectancy has improved

[edit] Losartan

  • Losartan is used for hypertension.
  • It is an angiotensin II type 1 receptor antagonist; that is, it keeps angiotensin II from binding to it's type 1 receptor.
    • Recall that angiotensin II causes increased activity of the triple-cotransporter at the renal tubules.
  • Losartan also blocks the actions of TGF‐β.
  • In a mouse model, losartan inhibits aortic aneurysms (unfortunately common in pts with Marfan syndrome).
  • Clinical trials are ongoing.
  • So we are treating at the TGF-beta level, not at the FBN1 level (which is where the lesion occurs).

[edit] Recent research

[edit] 5 important facts

  1. Autosomal Dominant 75% & 25% de novo mutations
  2. Allelic Heterogeneity
  3. Mutation in the Fibrillin‐1 (FBN1 found at 15q24.1)
  4. Fibrillin is found in the periosteum, Connective Tissues, and suspensor ligaments.
  5. TGF‐β signaling is upregulated in some forms of Marfan Syndrome

[edit] Not to be confused with

  • Mutations in FBN1 also cause:
    • Neonatal Marfan syndrome
    • Familial arachnodactyly
      • A disorder that is monosymptomatic because it only has long fingers.
    • Autosomal dominant ectopic lentis
    • MASS phenotype (Marfanoid signs involving mitral valve, aorta, skeletal, and skin).


  • So, like FGFR3, there is lots of heterogeneity when one looks at the gene.


  • Congenital contractural arachnodactyly (FBN2)
    • Clinical presentation overlaps a bit with Marfan syndrome
      • Arachnodactyly (really long, skinny fingers), pectus deformaties, scoliosis, etc.
      • Some young pts have aortic root dilitation
    • Caused by mutation in homologous gene to FBN1 (Marfan): FBN2.

[edit] Questions and answers

  • What are the requirements for a clinical diagnosis of Marfan Syndrome?
  • What signaling pathway is affected in Marfan Syndrome?
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