May24 M2-Genetic Disorders Involving the Spine and Limbs Flashcards
neural tube closes when + assoc problem
- day 20 to 25
- doesn’t close (gap or problem) = get a defect
ex of neural tube defect bc of failure of closure of neural tube (which, by definition, is the cause of neural tube defects)
spina bifida
cause of spina bifida
failure of fusion of vertebral laminae
spina bifida 3 clinical types
- spina bifida occulta
- meningocele
- myelomeningocele (most common)
spina bifida occulta def
- defect is covered by skin
- tuft of hair or birth mark or dimple at site of lesion
- asymptomatic otherwise, mild features
meningocele def
- meninges forced in gap between vertebrae
- variable, intermediate severity and symptoms
myelomeningocele def
- most serious and MOST COMMON type
- neural tissue is also present in the lesion (along with meninges)
spina bifida: why is it serious, what’s the problem (two-hit concept)
exposed nerves so get
- abnormal nerve development
- damage by amniotic fluid + direct trauma against uterine wall
clinical features of spina bifida
- paralysis
- bowel and urinary incontinence
- absence of sensation
- sexual dysfunction
what influences severity of symptoms in spina bifida
how high the lesion is
- higher = more consequences
- down as in sacrum = mild and still can walk
spectrum of presentaitons in spina bifida
can go from able to walk to nee assistive devices to walk (chair, etc.)
size of lesion + severity affects the symptoms
brain feature also seen in spina bifida
Chiari II malformation
- downward pulling on hindbrain (cerebellum) and herniation of hindbrain in spinal canal
- results in narrowing of opening for CSF circulation
- CSF buildup in ventricles called HYDROCEPHALUS
cause of Chiari II formation
at the level of the spina bifida lesion, CSF diffuses across membrane into amniotic fluid. this leads to a negative P in spinal canal which pulls down on hindbrain
in the case of hydrocephalus in spina bifida (caused by Chiari II malformation), what other complications may be present (caused by the hydrocephalus)
- developmental and learning disabilities.
- poor executive skills.
- breathing difficulties
genetics of spina bifida
- *most of them = isolated, developmental accidents + can run slightly in families. so most are SPORADIC or MULTIFACTORIAL
- can be part of a syndrome like trisomy 18 so SYNDROMIC
- can be associated with teratogens and teratogenic exposure (like maternal diabetes) so TERATOGENIC
environment and genetic factors interplay in spina bifida
if have relatives with it, liability curve shifted to the right so more chances of being above the threshold for getting the disease if you have enough environmental (risk) factors
4 things that the multifactorial threshold model (with curve of liability + threshold) implies in terms of recurrence
- incidence is greatest in relatives of most severely affected patients
- risk is closer among close relatives to index case (and decreases in more distant relatives)
- > 1 close relative affected = recurrence rate >10%., genetic load or risk factors increased. risk for relative increased
- if a patient of a certain gender has a disease that usually affects the other gender, the relatives of this patient are more at risk (bc many risk factors must have accumulated for this patient to be at risk)
one protective measure for spina bifida (to avoid recurrence)
folic acid supplementation of 0.4 mg a day (reduces neural tube defects)
folate is what
- water soluble vitamin
- required for DNA synthesis and repair
most common hereditary form of dwarfism
achondroplasia (short stature affecting long bones and caused by the spine)
clinical features of achondroplasia
- short stature
- large head
- scooped out nasal bridge
- rhizomelic (proximal) shortening of the limbs
- vertical or backwards forehead (not forward scoop)
- increased lumbar lordosis
- small hands and feet
- protuberant abdomen
additional features of achondroplasia
- excess skin folds
- trident hands (fingers all pointing outwards)
important thing to note about achondroplasia
- normal intelligence**
- relatively normal trunk length
complications of achondroplasia
- stenosis of foramen magnum
- leads to brainstem compression + hydrocephalus + lumbar spine stenosis possibly related to the lordosis
- recurrent otitis media bc of more horizontal eustachian tube
achondroplasia link with embryo dev of bone (and embryo lab)
- is a defect of endochondral bone formation
- leads to stenosis of the foramen magnum
skull bone where endochondral bone formation is happening
occipital bone
main clinical feature of achondroplasia in infant
- otitits media
- hydrocephalus
- brainstem compression
- obstructive apnea
main clinical feature of achondroplasia in later childhood and early adulthood
- symptomatic spinal stenosis
- genu varum
- obesity
- dental complications
- chronic otitis media
- brainstem compression
- LLD
achondroplasia in what group of disorders
skeletal dysplasias: a group of genetic disorders of skeleton caused by derangement of growth, dev and diff of skeleton
cause of skeletal dysplasia
mutations in FGFR3 (is a receptor so is TM)
penetrance of skeletal dysplasia and achondroplasia
complete penetrance (so nobody is a hidden normal carrier)
normal fct of FGFR3
- FGFR3 normally controls balance of bone growth and prolif tightly
- FGF binds it = cells do mitosis and differentiate and BONE GROWTH IS INHIBITED NORMALLY
specifics of the mutation in achondroplasia
- TM domain mutation
- constitutively active R. always in mode of shutting down and going towards terminal differentiation instead of allowing bone to grow
type of mutation that the TM mutation of FGFR3 is
gain of function
mutations in achondroplasia and the resulting aa substitution
- DNA level, 97% are G1138A and G1138C
- in the protein, this results in G380R mutation
- specific thing so easy to check with genetic testing*
inheritance pattern of achondroplasia
autosomal dominant (1 in 2 risk if one parent is affected)
2 mutations in FGF3R result
lethal (homozygous) (the skeletal dysplasia is too severe)
chances of having a normal child in achondroplasia
1 in 4
other diseases in the group of skeletal dysplasia
- hypochondroplasia (other mutation in FGFR3 causing intermediate disease)
- thanatophoric dysplasia (other mutation in FGFR3 causing severe skeletal dysplasia similar to that of homozygous achondroplasia. except is usually lethal but not always)
other way of getting achondroplasia than an affected parent
de novo mutation
charact of de novo mutations in achondroplasia
found that MOST OF THE TIME the mutation is in the father
-advanced paternal age is a risk factor for new autosomal dominant mutations
(imp) how to reduce recurrence risk in neural tube defects
- folic acid for prevention and risk reduction
- maternal serum screening and ultrasound (with possible termination of pregnancy) for prevention
(imp) how to reduce recurrence risk in achondroplasia
depends on families. not everyone wants genetic testing
