Genetic Disorders Flashcards
autosomal dominant
definition
only one good gene so heterozygotes
-will go thru all generations, both sexes
-may have delayed onset
-reduced production or inactive proteins
marfan syndrome gene problem
chromosome 15 (long arm) missense mutation in gene that encodes fibrillin-I
-no cystine for disulfide bonds, glycine instead so disordered = weak elasticity
auto dominant
fibrillin-I function
part of microfibrils aka elastic fibers in connective tissue
where fibrillin-I is found
- aorta (cardiovasc probs)
- suspensory ligament of lens (ocular probs)
- periosteum covering bones (skeletal)
fibrillin-1 mutation effects
- stiffening aortic wall
- inc TGF-beta1 activity
- inflamm, matric metallo proteases
- elastolysis, cell disarray
ocular symptoms marfan
displaced lens (ectopia lentis) so myopia
skeletal symptoms marfan
- long slender limbs (dolichostenomelia)
- pectus carinatum (pigeon)
- pectus excavatum (hollow chest)
- scoliosis
- spinder fingers (arachnodactyly)
- joint hypermobility
cardiovascular symptoms marfans
- mitral valve prolapse-mitral regurgitation
- dilation of ascending aorta @ root > valve incompetence > dissection/rupture
- cardiomyopathy- left vent enlarges as aorta widens
- congestive heart failure
criteria for marfan diagnoses
either 4 major features or 1 major 2 minor
major skeletal criterion
marfans
- pectus carinatum
- pectus excavatum (surgery)
- arm L greater than height (ULSR)
- wrist and thumb sign
- scoliosis or spondylolisthesis
- reduced elbow extension
- pes plenus
- protrusio acetabulae
other major criterion marfans
- lens dislocation
- dilation aortic root, dissection ascending aorta
- lumbosacral dural ectasia
- inheritance in family
minor criterion marfans
- pectus excavatum (no surgery)
- joint hypermobility
- high palate with dental
- crowding
- facial characteristics
- flat cornea
- mitral valve prolapse
- dilate pulmonary A or calcified mitral annulus below age 40
- recurrent or incisional hernia
mitral valve histology marfans
parachute appearance
-will close mid systole and hear click
-regurg into L atrium
cystic medial degeneration
marfans
elastic fibers are disrupted by pools of blue mucinous ground substance
type I and II ehlers danlos syndrome
classic
defective type V collagen, reduced amount
mutations in COL5A1/2 that encode alpha chain of type V
-reduced COL5A1 mRNA
type IV ehlers danlos syndrome
vascular
dec amount of type III collagen, collagen made but not exits the cell
-gene defect COL3A
-deadly
type VII ehlers danlos syndrome
arthrochalasia VIIa,b
cant turn procollagen into collagen
-amino terminal procollagen peptidase deficiency so cant cleave
EDS type I characteristics
-stretchy skin
-disorganized collagen, bear paw appearance
general EDS symptoms
- hyperelasticity- stretchy skin
- hypermobility- unusual extension, flexion of joints
- skin fragility- small injuries lead to serious wounds bc wound healing faulty
- sutures not hold well (dehiscence)
- tendency to bleed (bleeding diathesis type IV)
beighton scale for joint hypermobility
total score of at least 5 to dx
1 point for unilateral, 2 for bilateral
-flexion of 5th finger and thumb
-hyperextension elbow and knee
-forward flexion of trunk with knees full extended and palms on floor
neurofibromatosis type 1
NF1
highly variable expression + complete penetrance
-high mutation rate, half are new mutations
neurofibromin normal function
downregs function of p21 ras oncoprotein
-encodes GTPase activating protein that converts active ras-GTP to inactive ras-GDP
-aka when ras not inactivated = tumor
on chromosome 17q
expressions of NF1
-cafe au lait macules
-lisch nodules
-neurofibromas
-optic gliomas
-malignancies (malignant peripheral nerve sheath tumors from plexiform neurofibromas)
-learning disabilities
-scoliosis
only 10% or less dev malignancies
NF1 dx criteria
2+ present
1. 6 cafe au lait macules
2. freckling @ armpits or groin
3. 2+ neurofibromas OR 1 plexiform
4. 2+ lisch nodules @ eye
5. optic glioma
6. bone lesions (sphenoid, tibia)
7. first degree relative with NF
schwannoma vs neurofibroma
-schwannoma = only schwann cells, enculeate out , suppress nerve fibers
-neurofibromas = mix of schwann, perineurial, fibroblasts, and mast cells, prolif within nerve fibers (resection)
NF2 genetics
-20% of sporadic cases are actually mosaic for mutation
inactivating merlin/schwannomin tumor suppressor = NF2 associated and sporadic tumors
merlin function
bound to CD44 membrane signaling protein and actin
-will detatch from actin and inactivate Ras
symptoms of NF2
- bilateral vestibular schwannomas aka acoustic neuromas (impact CN VIII)
- low grade CNS tumors
- meningiomas
- ependymomas
- gliomas
criteria for definite NF2
- bilateral vestibular schwannomas OR family history of NF2
- plus unilateral schwannoma before 30 or any two of meningioma, glioma, schwannoma, juvenille posterior subcapsular lenticular opacities
criteria for probable NF2
- unilateral vestibular schwannoma before 30 + one of (miningioma, glioma, schwannoma, juvenille lenticular opacities)
- or 2+ meningiomas + unilateral vestibular schwannomas before 30 or one of (glioma, schwannoma, juvenille lenticular opacities)
presentation of symptoms NF2
hearing loss
-unilateral at onset > complete deafness
-VS also cause tinnitus, dizziness, imbalance
NF2 tumor appearance
multifocal or bunch of grapes
-VS more lobular and less vascular than sporadic
intracranial meningioma, spinal tumors, cutaneous tumors but more subtle than NF1
vestibular schwannomas
vestibular schwannoma features
- antoni A-dark staining, have verocay bodies (two lines of nuclei)
- antoni B- light staining
