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. | ||
- | http:// | + | http://www.kansasvolleyballassociation.org/images/flo_hyman.jpg |
===Mode of inheritance=== | ===Mode of inheritance=== | ||
Line 14: | Line 14: | ||
*'''25% de novo mutations''' | *'''25% de novo mutations''' | ||
*No Documented Cases of Non‐Penetrance | *No Documented Cases of Non‐Penetrance | ||
- | *Many different missense mutations have been observed (allelic heterogeneity). | + | *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. | *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) | **This resulted in a 93bp insertion between 8,379 & 8,380 (junction between exons 63 & 64) | ||
Line 20: | Line 20: | ||
===Single important gene=== | ===Single important gene=== | ||
*15q21.1: FBN1 gene codes for Fibrillin‐1 | *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 | *Fibrillin is present in the suspensory ligament, eleastic connective tissue (aorta & ligaments) and periosteum | ||
*320 kDa glycoprotein, 2,871 AA | *320 kDa glycoprotein, 2,871 AA | ||
Line 56: | Line 57: | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
+ | *Happloinsufficiency with dominant-negative effect. | ||
+ | **Both explain the pleiotrophy. | ||
===Phenotypic information=== | ===Phenotypic information=== | ||
+ | *A '''pleotropic disease''': affects several systems (skeletal, ocular, and cardiovascular). | ||
+ | *'''NB''': phenotype gets worse with age. | ||
====Ocular Abnormalities==== | ====Ocular Abnormalities==== | ||
Line 74: | Line 79: | ||
*Aortic Diliatation | *Aortic Diliatation | ||
**Enlargement | **Enlargement | ||
- | |||
**Regurgitation | **Regurgitation | ||
**Aneurysm | **Aneurysm | ||
Line 91: | Line 95: | ||
*Walker Murdoch http://yogatmanbarcelona.wordpress.com/2009/11/24/tu‐medula‐espinal‐ii‐lordosis/ Walker‐(wrists) | *Walker Murdoch http://yogatmanbarcelona.wordpress.com/2009/11/24/tu‐medula‐espinal‐ii‐lordosis/ Walker‐(wrists) | ||
*Steinberg (thumbs) | *Steinberg (thumbs) | ||
+ | *Make a fist and thumbs stick out | ||
+ | *Can easily wrap fingers around wrist with plenty of excess | ||
===Diagnosis=== | ===Diagnosis=== | ||
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*It is an angiotensin II type 1 receptor antagonist; that is, it keeps angiotensin II from binding to it's type 1 receptor. | *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. | **Recall that angiotensin II causes increased activity of the triple-cotransporter at the renal tubules. | ||
- | *Losartan also blocks the actions of TGF‐β. | + | *'''Losartan also blocks the actions of TGF‐β'''. |
*In a mouse model, losartan inhibits aortic aneurysms (unfortunately common in pts with Marfan syndrome). | *In a mouse model, losartan inhibits aortic aneurysms (unfortunately common in pts with Marfan syndrome). | ||
*Clinical trials are ongoing. | *Clinical trials are ongoing. | ||
+ | *So we are treating at the TGF-beta level, not at the FBN1 level (which is where the lesion occurs). | ||
===Recent research=== | ===Recent research=== | ||
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**Neonatal Marfan syndrome | **Neonatal Marfan syndrome | ||
**Familial arachnodactyly | **Familial arachnodactyly | ||
+ | ***A disorder that is '''monosymptomatic''' because it only has long fingers. | ||
**Autosomal dominant ectopic lentis | **Autosomal dominant ectopic lentis | ||
**MASS phenotype (Marfanoid signs involving '''m'''itral valve, '''a'''orta, '''s'''keletal, and '''s'''kin). | **MASS phenotype (Marfanoid signs involving '''m'''itral valve, '''a'''orta, '''s'''keletal, and '''s'''kin). | ||
+ | |||
+ | |||
*So, like FGFR3, there is lots of heterogeneity when one looks at the gene. | *So, like FGFR3, there is lots of heterogeneity when one looks at the gene. | ||
+ | |||
+ | |||
*Congenital contractural arachnodactyly (FBN2) | *Congenital contractural arachnodactyly (FBN2) | ||
**Clinical presentation overlaps a bit with Marfan syndrome | **Clinical presentation overlaps a bit with Marfan syndrome | ||
- | **Arachnodactyly (really long, skinny fingers), pectus deformaties, scoliosis, etc. | + | ***Arachnodactyly (really long, skinny fingers), pectus deformaties, scoliosis, etc. |
- | **Some young pts have aortic root dilitation | + | ***Some young pts have aortic root dilitation |
- | **Caused by mutation in homologous gene to FBN1: FBN2. | + | **Caused by mutation in homologous gene to FBN1 (Marfan): FBN2. |
===Questions and answers=== | ===Questions and answers=== | ||
*What are the requirements for a clinical diagnosis of Marfan Syndrome? | *What are the requirements for a clinical diagnosis of Marfan Syndrome? | ||
*What signaling pathway is affected in Marfan Syndrome? | *What signaling pathway is affected in Marfan Syndrome? |
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.
[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.
- Upregulated TGF‐β may result in:
- poor ECM remodeling
- lack of matrix deposition
- decreased matrix proteins
- elevated matrix degrading enzymes (MMPs)
- http://salamano‐giovanni.blogspot.com/2009/06/collagenopathies‐and‐marfan‐syndrome.html
- 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
- Ectopia Lentis
- Lens subluxation
- Glaucoma
- Myopia in 60%
- Retinal Detachment
- Premature Cataract Formation
- http://www.medstudents.com.br/original/revisao/marfan/marfan.htm
[edit] Cardiovascular Abnormalites
- Mitral valve prolapse
- Regurgitation
- Aortic Diliatation
- Enlargement
- Regurgitation
- Aneurysm
[edit] Skeletal Abnormalities
- Dolichostenomelia
- Pectus Excavatum
- Pectus Carinatum
- Scoliosis http://www.medicaltourismco.com/general‐surgery/pectus‐excavatum‐surgery‐abroad.
- http://www.nytimes.com/imagepages/2007/08/01/health/adam/9011Bowedchestpigeonbreast.html
- Thoracic Lordosis
- Narrow & highly arched Palate
- Joint laxity
- Arachnodactyly
- Walker Murdoch http://yogatmanbarcelona.wordpress.com/2009/11/24/tu‐medula‐espinal‐ii‐lordosis/ Walker‐(wrists)
- Steinberg (thumbs)
- Make a fist and thumbs stick out
- Can easily wrap fingers around wrist with plenty of excess
[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
- Autosomal Dominant 75% & 25% de novo mutations
- Allelic Heterogeneity
- Mutation in the Fibrillin‐1 (FBN1 found at 15q24.1)
- Fibrillin is found in the periosteum, Connective Tissues, and suspensor ligaments.
- 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.
- Clinical presentation overlaps a bit with Marfan syndrome
[edit] Questions and answers
- What are the requirements for a clinical diagnosis of Marfan Syndrome?
- What signaling pathway is affected in Marfan Syndrome?