May24 M2-Genetic Disorders Involving the Spine and Limbs

Question 1

neural tube closes when + assoc problem

Answer 1

• day 20 to 25

- doesn’t close (gap or problem) = get a defect

Question 2

ex of neural tube defect bc of failure of closure of neural tube (which, by definition, is the cause of neural tube defects)

Answer 2

spina bifida

Question 3

cause of spina bifida

Answer 3

failure of fusion of vertebral laminae

Question 4

spina bifida 3 clinical types

Answer 4

• spina bifida occulta
• meningocele
• myelomeningocele (most common)

Question 5

spina bifida occulta def

Answer 5

• defect is covered by skin
• tuft of hair or birth mark or dimple at site of lesion
• asymptomatic otherwise, mild features

Question 6

meningocele def

Answer 6

• meninges forced in gap between vertebrae

- variable, intermediate severity and symptoms

Question 7

myelomeningocele def

Answer 7

• most serious and MOST COMMON type

- neural tissue is also present in the lesion (along with meninges)

Question 8

spina bifida: why is it serious, what’s the problem (two-hit concept)

Answer 8

exposed nerves so get

• abnormal nerve development
• damage by amniotic fluid + direct trauma against uterine wall

Question 9

clinical features of spina bifida

Answer 9

• paralysis
• bowel and urinary incontinence
• absence of sensation
• sexual dysfunction

Question 10

what influences severity of symptoms in spina bifida

Answer 10

how high the lesion is

• higher = more consequences
• down as in sacrum = mild and still can walk

Question 11

spectrum of presentaitons in spina bifida

Answer 11

can go from able to walk to nee assistive devices to walk (chair, etc.)
size of lesion + severity affects the symptoms

Question 12

brain feature also seen in spina bifida

Answer 12

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

Question 13

cause of Chiari II formation

Answer 13

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

Question 14

in the case of hydrocephalus in spina bifida (caused by Chiari II malformation), what other complications may be present (caused by the hydrocephalus)

Answer 14

• developmental and learning disabilities.
• poor executive skills.
• breathing difficulties

Question 15

genetics of spina bifida

Answer 15

• *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

Question 16

environment and genetic factors interplay in spina bifida

Answer 16

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

Question 17

4 things that the multifactorial threshold model (with curve of liability + threshold) implies in terms of recurrence

Answer 17

1. incidence is greatest in relatives of most severely affected patients
2. risk is closer among close relatives to index case (and decreases in more distant relatives)
3. > 1 close relative affected = recurrence rate >10%., genetic load or risk factors increased. risk for relative increased
4. 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)

Question 18

one protective measure for spina bifida (to avoid recurrence)

Answer 18

folic acid supplementation of 0.4 mg a day (reduces neural tube defects)

Question 19

folate is what

Answer 19

• water soluble vitamin

- required for DNA synthesis and repair

Question 20

most common hereditary form of dwarfism

Answer 20

achondroplasia (short stature affecting long bones and caused by the spine)

Question 21

clinical features of achondroplasia

Answer 21

• 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

Question 22

additional features of achondroplasia

Answer 22

• excess skin folds

- trident hands (fingers all pointing outwards)

Question 23

important thing to note about achondroplasia

Answer 23

• normal intelligence**

- relatively normal trunk length

Question 24

complications of achondroplasia

Answer 24

• 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

Question 25

achondroplasia link with embryo dev of bone (and embryo lab)

Answer 25

• is a defect of endochondral bone formation

- leads to stenosis of the foramen magnum

Question 26

skull bone where endochondral bone formation is happening

Answer 26

occipital bone

Question 27

main clinical feature of achondroplasia in infant

Answer 27

• otitits media
• hydrocephalus
• brainstem compression
• obstructive apnea

Question 28

main clinical feature of achondroplasia in later childhood and early adulthood

Answer 28

• symptomatic spinal stenosis
• genu varum
• obesity
• dental complications
• chronic otitis media
• brainstem compression
• LLD

Question 29

achondroplasia in what group of disorders

Answer 29

skeletal dysplasias: a group of genetic disorders of skeleton caused by derangement of growth, dev and diff of skeleton

Question 30

cause of skeletal dysplasia

Answer 30

mutations in FGFR3 (is a receptor so is TM)

Question 31

penetrance of skeletal dysplasia and achondroplasia

Answer 31

complete penetrance (so nobody is a hidden normal carrier)

Question 32

normal fct of FGFR3

Answer 32

• FGFR3 normally controls balance of bone growth and prolif tightly
• FGF binds it = cells do mitosis and differentiate and BONE GROWTH IS INHIBITED NORMALLY

Question 33

specifics of the mutation in achondroplasia

Answer 33

• TM domain mutation
• constitutively active R. always in mode of shutting down and going towards terminal differentiation instead of allowing bone to grow

Question 34

type of mutation that the TM mutation of FGFR3 is

Answer 34

gain of function

Question 35

mutations in achondroplasia and the resulting aa substitution

Answer 35

• DNA level, 97% are G1138A and G1138C
• in the protein, this results in G380R mutation
• specific thing so easy to check with genetic testing*

Question 36

inheritance pattern of achondroplasia

Answer 36

autosomal dominant
(1 in 2 risk if one parent is affected)

Question 37

2 mutations in FGF3R result

Answer 37

lethal (homozygous) (the skeletal dysplasia is too severe)

Question 38

chances of having a normal child in achondroplasia

Answer 38

1 in 4

Question 39

other diseases in the group of skeletal dysplasia

Answer 39

• 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)

Question 40

other way of getting achondroplasia than an affected parent

Answer 40

de novo mutation

Question 41

charact of de novo mutations in achondroplasia

Answer 41

found that MOST OF THE TIME the mutation is in the father

-advanced paternal age is a risk factor for new autosomal dominant mutations

Question 42

(imp) how to reduce recurrence risk in neural tube defects

Answer 42

• folic acid for prevention and risk reduction

- maternal serum screening and ultrasound (with possible termination of pregnancy) for prevention

Question 43

(imp) how to reduce recurrence risk in achondroplasia

Answer 43

depends on families. not everyone wants genetic testing