Genetic diseases I Flashcards
What are the four categories of AD conditions?
- Quantitiy or arrangement of large sturctural proteins
- Regulatory proteins
- Deficiency in proteins that are in short supply
- Anti-oncogenes deleteion syndromes
Which AD category is Marfan?
- Quantitiy or arrangement of large sturctural proteins
- Regulatory proteins
- Deficiency in proteins that are in short supply
- Anti-oncogenes deleteion syndromes
Quantity or arrangement of large structural proteins
Which AD category is Ehlers’ danlos?
- Quantitiy or arrangement of large sturctural proteins
- Regulatory proteins
- Deficiency in proteins that are in short supply
- Anti-oncogenes deleteion syndromes
Quantity or arrangement of large structural proteins
Which AD category is huntingtons?
- Quantitiy or arrangement of large sturctural proteins
- Regulatory proteins
- Deficiency in proteins that are in short supply
- Anti-oncogenes deleteion syndromes
Regulator proteins and receptors
Which AD category is neurofibromatosis?
- Quantitiy or arrangement of large sturctural proteins
- Regulatory proteins
- Deficiency in proteins that are in short supply
- Anti-oncogenes deleteion syndromes
Anti-oncogene deletion
What is reduced penetrance?
Not every person who has the gene gets the disease
What is variable expressivity?
How well a gene is expressed if have it
What is the genetic defect in Marfans?
Missense mutation of FBN I at 15q21.1
What is the protein that is affected in Marfans?
Fibrillin I, the glycoprotein constituent of microfibrils (i.e. a component of elastic fibers)
Where is fibrillin I found?
Elastic fibers in Aorta
Suspensory ligaments of the lens
Periosteum
How does Marfans cause bone abnormalities?
Alteration in CT in periosteum making it more elastic
What is the amino acid change in Marfan?
Cys to Gly in the fibrillin protein
What happens to the aorta in Marfans d/t the mutated fibrillin 1?
Stiffening of the aortic wall
What happens to the TGF-beta in marfans d/t the mutated fibrillin 1?
Increased activity d/t loss of fibrillin
What happens to the inflammation and MMP regulation in marfans d/t the mutated fibrillin 1?
Increased inflammation
Increased MMP
What happens to the cell arrangement in marfans d/t the mutated fibrillin 1?
Elastolysis
Cell disrray
Is Marfans AD or AR?
AD
What are the heart problems seen in Marfans?
Mitral valve prolapse
Aortic dissection
Is nearsightedness (myopia) or farsightedness (hyperopia) common in pts with Marfan’s? Why?
Nearsightedness d/t degeneration of the lens
What is the lens defect in Marfans?
Ectopia lentis– Displace lens
What is dolichostenomelia seen in Marfans?
a human condition or habitus in which the limbs are unusually long
What are the two types of chest wall deformities seen in Marfans?
Pectus carinatum
Pectus excavatum
What is the back problem seen in Marfans?
Scoliosis
What is arachnodactyly, and which AD disease is it characteristic of?
a condition in which the fingers are abnormally long and slender in comparison to the palm of the hand.
Marfans
What is the joint issue seen in Marfans?
Hypermobility
That are the heart issues seen in Marfans? (4)
- Mitral valve prolapse (mitral regurgitation)
- Dilation of the ascending aorta/Aortic valve incompetence
- Cardiomyopathy
- CHF
Why is cardiomyopathy seen in Marfans?
As the aorta widens, the left ventricle enlarges, and cardiomyopathy ensures
What are the major criteria for diagnosing Marfans? (5)
- Pectus excavatum/carinatum
- Thumb signs
- Lens dislocation
- AAA
- Known mutation
Midsystolic click = ?
Mitral valve prolapse
What is mitral valve prolapse, and why is it seen in Marfans?
Bulging of the mitral valve back into the atrium
D/t messed up elastic fibers
Type A aortic dissection = ? Type B = ?
A = ascending B = descending
What is cystic medial degeneration?
Disruption of the elastic fibers–seen in AAA found in Marfans
What is the stain that highlight elastic fibers?
Silver stain
What is the problem with the aorta in Marfans besides dissection? What else does this cause?
Aortic root dilation–aortic regurgitation
How many of the 11 collagen types can be affected by Ehlers-danlos syndrome?
6/11
Types I and II of Ehlers-danlos syndrome are characterized by mutations in what genes? What collagen does this code for?
COL5A1(2) genes that encode the alpha chain of type V collagen
Type IV Ehlers-danlos syndrome is a defect in which gene/collagen?
COL3A1 gene, Type III (reticulin)
Type V and VI Ehlers-danlos syndrome have deficiencies in what?
Lysyl hydroxylase and lysl oxidase, an important enzyme in modifing collagen
Type VII Ehlers-danlos syndrome is due to what gene/protein malformation?
COL1A1/COL2A1 An amino-terminal procollagen peptidase deficiency, thus cannot turn procollagen into collagen
Which tpye of Ehlers-danlos syndrome is the most deadly? Why?
Type IV b/c type III collagen is found in all organ systems
Which two types of Ehlers-danlos syndrome are AR?
IV, and VIIc
Which type of Ehlers-danlos syndrome causes kyphoscoliosis?
IV`
WHich type of Ehlers-danlos syndrome causes vascular problems?
IV
Type I/II Ehlers-danlos syndrome is due to what gene defect? What does this cause?
COL5A1 mRNA reduced
What is the problem with type IV Ehlers-danlos syndrome?
COL3A gene defect, causing collagen 3 to be unable to leave the ER
Type VII Ehlers-danlos syndrome is due to what gene defect? What does this cause?
COL1A1/COL1A2 gene defect, causing collagen 1 to not be cleavable
What are the histological characteristics of collagen in Ehlers-danlos syndrome?
Disorganized collagen
Bear claw collagen = ?
Type I Ehlers-danlos syndrome
What is the skin like in Ehlers-danlos syndrome?
Fragile (cigarette paper skin)
What are the complication of the skin characteristics in Ehlers-danlos syndrome?
Sutures don’t hold well (dehiscence of surgical wounds)
Bleed easily
What is the characteristic of the joints of pts with Ehlers-danlos syndrome?
Hypermobile, with increased angle between joints
What is the Beighton scale for joint hypermobility?
various joint hyper mobilityfindings rated 1 if unilateral, 2 if bilateral
What is the mutated gene in NF1? Which chromosome is this on? What does this code for?
NF1 gene on 17q
Codes for neurofibromin
What is the function of neurofibromin?
Down regulates p21 ras oncoprotein by deativating ras-GTP to ras-GDP
What are the four classic symptoms of NF1?
- Axillary/inguinal freckling
- CALMs
- Lisch nodules
- Neurofibromas
What is the penetrance and expressivity of NF1?
100% penetrance, but highly variable expression
What is the signal that ras is involved in?
GF signalling
What are the less common symptoms of NF1? (3)
Neurofibromas
Optic gliomas
Learning disabilities
True or false: NF1 has been associated with Wilms tumor and rhabdomyosarcoma
True
What fraction of pts with NF1 have only mild cutaneous involvement?
2/3
What are the seven diagnotic criteria for NF1?
- Six or more CALMs
- Freckling of the axilla/inguinal area
- More than one Neurofibromas
- More than two lisch nodules
- Optic glioma
- Distintive bone lesions
- Family member has it
What are lisch nodules seen inf NF1?
Harmartomas of the iris
True or false: neurofibromas can occur anywhere on the body
True
Where can neurofibromas grow? (2)
Skin
Nerve sheaths
What is the difference between a neurofibroma and a Schwannoma?
Neurofibroma is made up of many different types of, whereas schwannomas are made up solely of Schwann cells
Which can be shelled out during surgery: Schwannomas or neurofibromas?
Schwannomas
Spindle cell morphology can be seen in what AD discussed?
NF1
What is the tumor that NF1 pts are predisposed to?
Malignant peripheral nerve sheath tumors (MPNSTs)
What is the gene in NF2? Which chromosome is this on? What protein does this code for?
22q
NF2 gene
Merlin/schwannomin
What are the path/symptoms of NF2? When does these present?
Acoustic neuromas (hearing loss/tinnitus) 3rd decade of life
What is the function of merlin/schwannomin?
ras suppressor
What triggers merlin protein normally?
CD44 binding
What are the two major malignancies seen in NF2?
Bilateral vestibular schwannomas
Meningiomas
What is the diagnostic criteria for NF2?
Bilateral vestibular schwannomas
OR
One vestibular schwannoma with another -oma
What is the pathology of NF2? When does these present?
Acoustic neuromas (hearing loss/tinnitus) 3rd decade of life
What are the symptoms of NF2? (4)
Hearing loss
Tinnitus
HA
Balance disturbance
What do the acoustic neuromas look like grossly?
Bunches of grapes (just like staph aureus!!)
What are the two histological patterns of vestibular schwannomas?
Antoni A and B
Bunches of collagen (antoni A or B)?
Antoni A
Mixed CT (antoni A or B)?
B
What are verocay bodies? What are these found in?
Palisading tumor cells with CT between them
Found in NF2 vestibular schwannomas
