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Flashcards in X-linked Deck (46):
1

Mechanism of X chromosome inactivation -

XIST gene located on the X chromosome

expressed only from the inactive X

required for X inactivation

2

Hypophasphatemic rickets
inheritance
incidence

X-linked dominant
1/20,000

3

Hypophosphatemic rickets
clinical

low phosphate in blood
short stature
bone deformity

4

Hypophosphatemic rickets
mutation?

PHEX
Regulates fibroblast growth factor
Inhibits kidneys ability to reabsorb phosphate into the blood stream

5

Fragile X
inheritance
mutation?

X linked dominant
FMR1

6

Fragile X
mutation issue?

trinculeotide repeat
CGG

7

Fragile X
incidence
m and f

m
1/2500-4000
f
1/7000-8000

8

What is the most common caused of inherited developmental delay?

fragile x

9

Since fragile x is a trinucleotide repeat, what do we see?

anticipation

10

fragile x
parental bias

mom

11

fragile x
clinical

intellectual
dysmophic: large ears, long face, macroorchidism
autistic
anxiety
hand flapping biting
aggression

12

fragile x premutation FMR1 associated conditions?

Fragile x associated tremor ataxia FXTAS - white matter lesion on MRI / intention tremor / gait ataxia

FMR1 -related primary ovarian insufficiency - menopause

13

fragile x CGG thresholds

6-45 normal
46-55 grey
56-200 Premutation (FXTAS/POI)
>200 full mutation

14

Rett Syndrome
inheritance?
incidence
new mutation?

X linked dominant
1/10,000
95%

15

Rett
clinical?

loss of normal coordination
acquired microcephaly
loss of communication
failure to thrive
seizures
abnormal hand movement

16

Rett
mutation?

MECP2
MethyL CpG binding protein
Essential for normal function of nerve cells

17

Lesch Nyhan
inheritance
incidence

X linked recessive
1/380,000

18

Lesch Nyhan
Clinical?

cerebral palsy
cognitive/behavior
overproduction uric acid
self injury

19

Lesch Nyhan mutation?

HPRT1
Hypoxanthine phosphoribosyltransferase 1
Recycling of purines

20

Dytrophinopathies
inheritance
what are they
3 examples

x-linked recessive
spectrum of muscle diseases from mild to severe

Becker MD
Duchenne MD
DMD associated dilated cardiomyopathy

21

Dystrophinopathies
Mutation?
Loci?

DMD
Xp21-21.1
dystrophin

22

What is the largest human gene?

dystrophin

23

Duchenne
Clinical

progressive muscle weakness from proximal to distal
calf hypertrophy
dilated cardiomyopathy
CK level 10x normal
onset before 5
wheelchair bound before 13
death in 30s
absence of dystrophin

24

Becker
Clinical

Progressive muscle weakness proximal > distal
dilated cardiomyopathy
CK levels 5x normal
later onset
wheelchair bound after 16
death in 40s
abnormal quality dystrophin

25

DMD associated DCM
Clinical

dilated cardiomyopathy presenting between 20-40
early death
no skeletal muscle involvement
no dystrophin in myocardium

26

Hemophilia A
inheritance
incidence
carrier females affected?

x linked recessive
1/4000 male births
10% carrier females affected

27

Hemophilia A
clinical

blood disorder where blood fails to clot due to deficient factor VIII
Spontaneous bleeds into joints, muscles, or intracranial
excessive bruising
prolonged bleeding
delayed wound healing
royal family

28

Hemophilia A
gene mutated?

F8
Xq28
Deficient factor VIII

29

50% hemophila A is due to?

22A inversion

30

Mitochondrial DNA
#genes

37

31

Characteristics of mtDNA (4)

maternal inheritance
replicative segregation
homoplasmy/heteroplasmy
threshold effect

32

mtDNA
Replicative segregation

At cell division the multiple copies of mtDNA replicate and sort randomly among newly synthesized mitochondria

this could be normal or mutated DNA

33

Heteroplasmy

Cells have both mutant and normal mitochondria / threshold for if phenotypic consequence

34

mitochondrial disease tends to affect tissues that?

Rely on oxidative phosphorylation
brain
retina
skeletal muscle
heart

35

mitochondrial diseases (4)

Kearns-Sayre syndrome
MELAS
MERRF
Leber Hereditary Optic Neuropathy

36

Kearns Sayre Syndrome
incidence

mtDNA - large deleation (usually removes 12 genes)
1-3/100,000
Most commonly caused by somatic mutation

37

Kearns Sayre
clinical

triad
- pigmentary retinopathy
- progessive external ophthalmoplegia
- onset before 20

cardiac conduction defects
ataxia
deafness
kidney problems

38

MELAS
Mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes

inheritance
incidence
new mutation?

mitochondrial

1/300,000

low new mutation

39

MELAS
clinical

2-10y/o
muscle weakness
seizures
repetetive stroke like episodes
elevated lactic acidosis

40

MELAS Mutations?

Mitochondrial genes
MT - ND1/ND5/TH/TL1 (80%) /TV)

41

MERRF
Myocloinic epilepsy with ragged red fibers

mt
1/400,000
low new mutation

42

MERRF
CLINICAL

muscle symptoms
seizures
ataxia
dementia
ragged red fibers

43

MERRF
Mutation?

mitochondrial genes
MT-TK

44

Leber Hereditary Optic Neuropathy

mt
1/30-50,000 europeans

45

Leber Hereditary Optic Neuropathy

bilateral subacute vision failure
occurs during young adulthood

46

Leber Hereditary Optic Neuropathy
Mutation?

mt DNA
point mutations