X-linked Flashcards
Mechanism of X chromosome inactivation -
XIST gene located on the X chromosome
expressed only from the inactive X
required for X inactivation
Hypophasphatemic rickets
inheritance
incidence
X-linked dominant
1/20,000
Hypophosphatemic rickets
clinical
low phosphate in blood
short stature
bone deformity
Hypophosphatemic rickets
mutation?
PHEX
Regulates fibroblast growth factor
Inhibits kidneys ability to reabsorb phosphate into the blood stream
Fragile X
inheritance
mutation?
X linked dominant
FMR1
Fragile X
mutation issue?
trinculeotide repeat
CGG
Fragile X
incidence
m and f
m
1/2500-4000
f
1/7000-8000
What is the most common caused of inherited developmental delay?
fragile x
Since fragile x is a trinucleotide repeat, what do we see?
anticipation
fragile x
parental bias
mom
fragile x
clinical
intellectual dysmophic: large ears, long face, macroorchidism autistic anxiety hand flapping biting aggression
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
fragile x CGG thresholds
6-45 normal
46-55 grey
56-200 Premutation (FXTAS/POI)
>200 full mutation
Rett Syndrome
inheritance?
incidence
new mutation?
X linked dominant
1/10,000
95%
Rett
clinical?
loss of normal coordination acquired microcephaly loss of communication failure to thrive seizures abnormal hand movement
Rett
mutation?
MECP2
MethyL CpG binding protein
Essential for normal function of nerve cells
Lesch Nyhan
inheritance
incidence
X linked recessive
1/380,000
Lesch Nyhan
Clinical?
cerebral palsy
cognitive/behavior
overproduction uric acid
self injury
Lesch Nyhan mutation?
HPRT1
Hypoxanthine phosphoribosyltransferase 1
Recycling of purines
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
Dystrophinopathies
Mutation?
Loci?
DMD
Xp21-21.1
dystrophin
What is the largest human gene?
dystrophin
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
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
DMD associated DCM
Clinical
dilated cardiomyopathy presenting between 20-40
early death
no skeletal muscle involvement
no dystrophin in myocardium
Hemophilia A
inheritance
incidence
carrier females affected?
x linked recessive
1/4000 male births
10% carrier females affected
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
Hemophilia A
gene mutated?
F8
Xq28
Deficient factor VIII
50% hemophila A is due to?
22A inversion
Mitochondrial DNA #genes
37
Characteristics of mtDNA (4)
maternal inheritance
replicative segregation
homoplasmy/heteroplasmy
threshold effect
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
Heteroplasmy
Cells have both mutant and normal mitochondria / threshold for if phenotypic consequence
mitochondrial disease tends to affect tissues that?
Rely on oxidative phosphorylation brain retina skeletal muscle heart
mitochondrial diseases (4)
Kearns-Sayre syndrome
MELAS
MERRF
Leber Hereditary Optic Neuropathy
Kearns Sayre Syndrome
incidence
mtDNA - large deleation (usually removes 12 genes)
1-3/100,000
Most commonly caused by somatic mutation
Kearns Sayre
clinical
triad
- pigmentary retinopathy
- progessive external ophthalmoplegia
- onset before 20
cardiac conduction defects
ataxia
deafness
kidney problems
MELAS
Mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes
inheritance
incidence
new mutation?
mitochondrial
1/300,000
low new mutation
MELAS
clinical
2-10y/o muscle weakness seizures repetetive stroke like episodes elevated lactic acidosis
MELAS Mutations?
Mitochondrial genes
MT - ND1/ND5/TH/TL1 (80%) /TV)
MERRF
Myocloinic epilepsy with ragged red fibers
mt
1/400,000
low new mutation
MERRF
CLINICAL
muscle symptoms seizures ataxia dementia ragged red fibers
MERRF
Mutation?
mitochondrial genes
MT-TK
Leber Hereditary Optic Neuropathy
mt
1/30-50,000 europeans
Leber Hereditary Optic Neuropathy
bilateral subacute vision failure
occurs during young adulthood
Leber Hereditary Optic Neuropathy
Mutation?
mt DNA
point mutations
