Unstable Repeats

Question 1

mechanism of unstable repeats?

Answer 1

slipped mispairing of DNAP

Question 2

what is the consequence of mitotic instability?

Answer 2

phenotypic variability

Question 3

what diseases is mitotic instability most severe?

Answer 3

fragile X
myotonic dystrophy
friedrich ataxia

Question 4

how is HD inherited?

Answer 4

autosomal dominant

Question 5

does HD manifest differently with age?

Answer 5

age-related penetrance.

more repeats –> younger age

Question 6

is there variable expressivity in HD?

Answer 6

yes

Question 7

what are the symptoms of HD?

Answer 7

chorea
dystonia
personality changes
gradual loss of cognition
death

Question 8

normal, premutation, borderline, affected repeat #

Answer 8

normal = 40

Question 9

when does anticipation occur?

Answer 9

when father is carrier

Question 10

pathology behind HD?

Answer 10

expansion in exon 1 of huntington gene

confers novel property in protein that causes it to accumulate in neurons –> death

Question 11

how frequent is fragile X

Answer 11

most common form of inherited MR

Question 12

how is fragile X inherited?

Answer 12

X linked

loss of function

Question 13

phenotype of X linked/

Answer 13

mental retardation
hyperactivity and autism
speech delay
long narrow face/large ears/big jaw
macroorchidism

Question 14

normal, premutation, affected repeat numbers

Answer 14

normal = 200

Question 15

what if you have a premutation?

Answer 15

males get FXTAS

females get POI

Question 16

clinical features of FXTAS

Answer 16

late onset cerebral ataxia w/ parkinsonism
dementia
executive fxn deficits

Question 17

when does anticipation occur?

Answer 17

PSYCH! anticipation doesn’t technically occur because can’t be passed on by father. BUT

if mother is carrier of premutation will see expansion

Question 18

are heterozygous females affected?

Answer 18

50% have MR
less severe than in males
no risk of POI
skewed X inactivation in brain makes it worse

Question 19

how do you diagnose repeat disorders?

Answer 19

PCR and southern blot

Question 20

how is myotonic dystrophy inherited?

Answer 20

autosomal dominant

gain of function

Question 21

what is the phenotype of myotonic dystrophy

Answer 21

myotonia
cataracts
hypogonadism
diabetes
frontal balding

Question 22

what is the genotype of myotonic dystrophy

Answer 22

triplet in 3’ UTR of DMPK

Question 23

what is the range of phenotypes?

Answer 23

normal
premutation
mildly affected
classically affected
severely affected

Question 24

does anticipation occur?

Answer 24

when passed on from mother can get MASSIVE expansions

Question 25

how is friedreich ataxia inherited?

Answer 25

autosomal recessive

loss of function

Question 26

what is the phenotype of friedreich ataxia?

Answer 26

incoordination of limb movements
speech difficulty
impairment of position and vibratory sense
cardiomyopathy
scoliosis
manifests prior to adolescence

Question 27

genotype of freidrich ataxia?

Answer 27

triplet in intron of frataxin (Fe metabolism)

rarely see compound heterozygote w/ expansion + point mutation

Question 28

anticipation in freidrich ataxia?

Answer 28

NO!

autosomal recessive