Final Flashcards
(169 cards)
1
Q
Principle of Segregation
A
occur in pairs and only one member of the pair is transmitted to the offspring
2
Q
Independent Assortment
A
Genes at different loci are transmitted independently
3
Q
__% genetic diseases are located on autosomes
A
95
4
Q
characteristics
A
Autosomal Dominant Inheritance Pattern
@ least 1 affected parent
can affect either sex
txmit by either sex
5
Q
child of an affected x unaffected in an auto-dom inherit is __ chnace of being affected
A
50%
6
Q
examples of auto-dom inheritance pattern (10)
A
“dominatrix” - AHH, PORN FAM
Acute Intermittent Porphyria (PBGD)
Huntington Disease (HTT)
Hereditary Nonpolyposis Colon Cancer (HNPCC, MSH2, MLH1,PMS1/2)
Postaxial Polydactyly (GLI3)
Osteogenesis imperfecta type 1 (COL1A1/2)
Retinoblastoma (RB1)
Neurofibromatosis Type 1 (NF1)
Familial hypercholesterolemia (LDLR)
Achondroplasia (FGFR3)
Marfan syndrome (FBN1)
7
Q
huntintons
A
CAG tri-nt repeat in HTT gene in chr 4
- singal, txp, protection from apop
late onset: 35-44 y/o
- dmg corpis striatum
- chorea (abnormal, involuntary writhing mvmts)
- loss of motor control
- behavior/mood/personality changes
8
Q
penetrance
A
porportions of individuals carrying variant with associated phenotype
9
Q
age of onset of huntington’s relationship
A
largers # repeats = earlier age of onset
10
Q
Huntington Disease (HD)
A
11
Q
Familial Hypercholesterolemia
A
LDLR in chr 19
- high blood LDL –> high CAD @ young age
- hetero = reduced fx LDLRs
most common auto-dom disorder
- thickened achilles
- choles deposits in soft tissue
- xanthalasma (eye)
- xanthomas (on tendons)
- arcus cornealis (grey spot in iris)
12
Q
Hereditary Nonpolyposis Colon Cancer (HNPCC): Lynch Syndrome
A
mismatch repair: MLH1 (chr 2), MSH2 (chr 3), PMS1 (chr 2), PMS2(chr 7)
- locus heterogeneity
–> incr freq of colon/endomet ca
13
Q
what is locus hetergeneity
A
mutations in different genes resulting in same phenotype
14
Q
Postaxial Polydactyly
A
GLI3 in chr 7
- Ts in shaping of organs/tissues during dev –> extra fingers and toes
may exhibit:
- reduced penetrance
- variable expressivity (extra digit may be small skin tag to fully formed digit)
15
Q
Achondroplasia
A
FGFR3 in chr 4
- txmemb RTK that binds fibroblast GF
- most cases are due to new mutations
characteristics:
- short limbs with normal torso
- prominent forehead
- flat nasal bridge
- redundant skin folds in arms and legs
16
Q
Achondroplastic dwarfism
A
Pedigree of a mating between two
patients with achondroplasia
17
Q
marfans
A
FBN1 in chr15: fibrillin in CT (affects elastin deposit)
MANY mutations
- missense = most severe
- dominate negative effect:
- mut fibrillins bind and disable normal
pleiotropism
- multi pheno effects of a single gene
- ocular, skeletal, CV
characteristics
- myopia, ectopia lentis
- tall with long and slender limbs
- joint hypermobility
- MVP, asc aorta dilation
18
Q
A
Autosomal Recessive Inheritance Pattern
- affected child born to UNAFFECTED parents
- parents usually carriers but ASYMPTOMATIC
- incr rate in consaguinous parents
- can affect either sex
19
Q
proband
A
affected indi
20
Q
recurrance risk of an auto-recessive diseases for each sibling of proband is…
A
25%
21
Q
Examples of Diseases with Autosomal Recessive Inheritance Pattern
A
TAX CAT NAPS
Tay-Sachs Disease (HEXA)
Ataxia telangiectasia (ATM)
Xeroderma pigmentosum (XP)
Cystic fibrosis (CFTR)
Albinism (TYR)
Thalassemia
Niemann-Pick Disease (SMPD1)
Alkaptonuria (HGD)
Phenylketonuria (PAH) - “PKU”
Sickle cell anemia
22
Q
CF
A
CFTR in chr 7: delta-F508 is most common
- most common auto-recess disease in caucasians
fx:
- Cl- channel: salt and water balance
- affects lungs, panc
23
Q
classic PKU
A
PAH (phenylalanine hydroxylase) in chr 12
- most common inborn error of aa metab
- mousy body odor
char:
- HYPOpig due to lack of tyr
- mental retard (if untx/undx)
tx:
- limit phe and supplement with tyr, trp, and BCAA (leu, ile, val)
24
Q
incomplete/reduced penetrance
A
some people with mutation DO NOT show symptoms/phenotype
25
compelx disease
complex inheritance pattern (can cluster in fam but NOT mendelian)
polygenic: genetic predisposition (susceptibility) likely due to particular combo of genes
multifactoral: int-act genes and environ
26
In multifactorial disorders, there is a \_\_\_\_\_\_, above which a person will develop the multifactorial disorder
threshold
27
adoption studies
same gene bg with different environ
* INCR freq in adoptive = higher environ influ
* INCR freq in bio = high bio influ
28
family rel-ships and % of genes in common
1st degree: 50
* parents, sib, children
2nd degree: 25
* aunt/uncle, niece/nephew, grandp, half-sib
third degree: 12.5
* first cousins
29
Relative risk ratio
\>1: relative more likely to dev disease
\<1: relative has SAME likelihood to dev disease as any other indiv in population
30
concordance
2 indiv in fam share a trait or have same disease
31
concordance rate
proportion of pairs of indiv (twins) who share train or have same disease
32
twin studies
100% concordance in monozyg = genotype alone is sufficient to dev disease
* sickle cell
\<100% concordance in monozyg = nongenetic factors play a role in disease dev
monozyg twins reared apart
* high concordance = genetic
* low concordance = environ
33
Greater concordance in MZ versus DZ is strong evidence for a ______ component to the disease
genetic
34
If low concordance in MZ and DZ twins (especially if other siblings affected), evidence for strong contribution of \_\_\_\_\_\_\_\_
post-uterine environment
35
GWAS and SNPS assoc with disease suscep genes
Common disease, common variant theory
* suscep alleles = mod risk and occur at HIGH freq in pop
* disease will be common in in large pop of unrelated indiv
* **use SNP microarray**
36
DM2
GWAS IDed \>38 SNPS
* common varients: TCF7L2 and SLC30A8
* GK varients = incr fasting gluc lvls
**associated SNPS = 10% of herit**
37
SLC30A8
beta-cell zinc transporter, ZnT-8 (ONLY expr in panc islet cells)
* txp zinc from cytop into insulin secr vesicles
* zinc req for insulin storage and secretion
varient: rs13266634: arg --\> trp change at pos 325 = insulin secr defect
38
TCF7L2
"open chromatin sites"
* greater enhancer activity --\> incr Ts of gene (5x in DM@)
carriers
* most likely to fail sulfonylurea than metformin
* MORE likely to be on insulin therapy than diet alone
39
char of x chrom
155 x 10^6 bp's --\> 1100 genes
* 800 protein coding
* 300 RNA
40
lyon hypothesis
x inactivation: one of x chr in females randomly inactiv early in emb dev
41
dosage compensation
ensures that eq amts of x-linked genes prod in males and females
42
Characteristics of X-linked Recessive Disorders
males affected IF they get mut x chr copy
females RARELY show signs due to having 2 copies
MOTHER is usually asympt carrier
NO male-male txmission
43
Examples of X-linked Recessive Diseases
**OH, DR Hunter G**ets **F**ree **M**oose **L**icenses
Ornithine Transcarbamoylase (OTC) Deficiency
Hemophilia A (F8)
Duchenne muscular dystrophy (DMD)
Red-Green Color blindness (OPN1LW, OPN1MW)
Hunter Syndrome (IDS)
G6PD Deficiency (G6PD)
Fabry Disease (GLA)
Menkes syndrome (ATP7A)
Lesch-Nyhan syndrome (HPRT)
44
DMD
DMD: X-chr - can detect location of mut in multiplex PCR
symp usually seen by age 5
degen of M fibers
* M replaced by fat and CT
* **pseudohypertrophy** of calf M
* creatine kinase released by M = early dx indicator, ay be 20x higher
* chr inflam cells
* usually affects heart and respir --\> COD by 25
45
G6PD
**x-linked**
regulated step in HMP/PPP shunt --\> prod NADPH to protect RBCs from ROS
mutation --\> hemolysis --\> hemolytic anemia
* progressive yellowing of sclera and skin
* bulging tympanic memb
46
hemophilia A
factor VIII: intrinsic pathway of blood clotting
* affects fibrin formation
* prolonged bleeding
47
red-green color blindness
x-linked
photoreceptor cells in retina
* rods: light-absorbing rhodopsin
* cones: opsins for trichromatic color vision
**red-green = most common defect in color perception**
48
49
dgree of red/green color perception depends on...
where crossing over occurs during meiosis
50
char of X-linked Dominant Disorders
only ONE copy of defective x-chr required
* males MOST severly affected --\> may be lethal
* females = carriers = 50% chance of txmit to offspring
51
x-linked
## Footnote
in EVERY gen but MALES more likely affected
52
examples of x-linked dom diseases
rett
fragile-x
53
rett syndrome
**x-linked dom**
autism spectrum disorder observed mainly in FEMALES
* lethal in males: miscarriage
MeCP2
* normal: bind methlyated cyt --\> gene silence
* mutation: ABNORM activation of genes usually silenced
54
fragile-x syndrome: x-linked dom
* CGG tri-nt expansion in 5'UTR of FMR1 gene
* normal = 6-50
* mut = **\>200 repeats** - detect via southern blot
MOST common form of inherited MALE mental retard
55
Factors that affect expression of disease-causing gene and may complicate inheritance pattern
1. variable expressivity
2. incomplete penetrance
3. skewed x-inactivation
56
conseq of x-inactivation
can result in manifesting heterozyg if ALL of **active** x-chr happen to be one carrying disease-causing
* can be why mother does not exhib disease that DAUGHTER expresses
57
Y Chromosome
60 x 10^6 bp's --\> \<100 genes and 2 dozen distinct proteins
58
•Pseudoautosomal region (PAR)
site of recombination with X chromosome
* pair with x-chr during meiosis
* shares homology
59
SRY
Sex-determining region of the Y
encodes testis-detm fac (TDR) that trig testes formation
60
USP9Y, DDX3Y, DAZ genes
invovled in spermatogenesis (azoospermia factors)
Microdeletions in these regions observed in males with azoospermia (AZF)
61
SRY and sex reversal
if error in meiosis results in x-over OUTSIDE of PAR --\> usually involves SRY since it is close to PAR
IF SRY x-over to x-chr --\>
* XY female: incomplete masculinaization
* XX male: virilzation
* **ambiguous genitalia**
62
y-linked disease
txmission is **EXCLUSIVELY** male-male
63
DFNY1 gene
y-linked
hearing loss
64
Basic Decision Tree for Determining the Mode of Inheritance
in a Pedigree
65
If transmission occurs only thru affected mothers and never thru affected sons, the pedigree is likely to reflect....
mitochondrial inheritance
* Affected women transmit to **all** of their offspring
* Affected men transmit to **none** of their offspring
66
probability
chance/likelihood specific outcome/event WILL occur relative to all the possible outcomes
67
probability is calc as...
68
multiplication rule
If two or more events are independent, the chance that they will **occur together** is the PRODUCT of their separate probabilities
ex: sex of child at each birth is INDEP of sex of previous child
* prob of 3 sons in a row? 1/2 x 1/2 x 1/2 --\> 1/8
69
what is the probability of having 3 sons in a row if a couple already has 2 sons?
1/2
since first 2 sons are alread yborn, these are NO LONGER probabilities
70
addition rule
If we want to know the probability of either one outcome OR another, this is the sum of their separate probabilities
71
What is the probability of having 2 sons or two daughters in a row?
½ x ½ = 1/4 (2 sons in a row)
½ x ½ = 1/4 (2 daughters in a row)
1/4 + 1/4 = 1/2 probability of two sons or two daughters in a row
72
What make the differences in drug responses
1. physical condition
2. genetic individuality
73
Pharmacogenetics
study how variations in gene(s) affects response to rug therapy
74
human genom
3 billion nucleotides
About 21,000 protein-coding genes
100,000 proteins (or more)
75
•Every two people differ:
1 in every 1,000 nucleotides in their genome
MAJORITY = SNPs
76
enz involved in drug metab
phase 1: oxidation/reduction
phase 2: conjugation
77
types of metabolizers
ultra: multiple copies of active gene
extensive: 2 normal genes
intermediate: 1 active, 1 non-active
poor: non-f/less fx gene = slow drug metab
78
prodrug
bio inactive cmpd that needs to be metab in body to produce active drug
79
prodrugs and differences in metab in poor and ultra metabolizers
poor:
* poor efficacy
* poss **accumulation** of prodrug
ultra:
* good efficacy
* rapid effect
80
active drug metabolism differences b/w poor and ultra metabolizers
poor:
* good efficacy
* may need lower dose since accumulation of active drug can produce adverse effects
ultra:
* poor efficacy
* needs GREATER dose or slow release since metab is so fast
81
tamoxifen
tx: early/adv estrogen receptor positive breast ca
tamoxifen --\> CYP2D6 --\>
* 4-OH TAM --(CYP3A 4/5) --\> **endoxifen (active)**
* **endoxifen (active)**
variations in CYP2D6 most important variable!!
82
CYP2D6
chr 22: one of major drug metab enz
egyptians have a high rate (30%) of pop that are ultra-rapid metabolizers
83
examples of drugs that undergo CYP2D6
codeine (prodrug) --\> morphine (active)
nortriptyline (active) --\> OH-nortriptyline (inactive metabolite)
84
purine analogs
1. azathiopurine
* immuno-suppressive: organ txplant, autoimm
2. 6-mercaptopurine (6-MP)
* chemotx: acute lymphocytic leuk
85
TPMT
phase II enz
* variations can affect tox of purine analogues
* decrease TPMT --\> INCR tox of 6-MP
86
NAT-2 metablizes...
isonizaid (active) --\> acetyl isonizaid (inactive metab)
87
drug targets
specific target protein a drug effects
88
zileuton affects what protein?
5-lipoxygenase
89
gefitinib affects what protein?
EGFR
90
zileuton
anti-asthma
* inhib 5-lipoxygenase (ALOX5)
* genetic VNTRs of ALOX5 in promotor region can result in expr of different amts of target protein
* mut: ABT-761 - responds LESS well due to LESS protein made
91
polymorphisms of Gefitinib
only small portions of non-small-cell lung carcinoma respond well
* tumors has gain-of-fx mutation in ADP binding site of EGFR
* pts of east asian origin respond better than caucasians
92
warfarin
what is it metab by?
anticoag
* metab by: VKORC1 & CPY2C9
93
goals of personalized medicine
RIGHT:
* pt
* drug
* dose
* indication
* time
94
examples of personalized drugs
* 6-MP (leukemia, Metabolism: TPMT)
* Herceptin (breast cancer, target: Her2/neu)
* Erbitux (colorectal cancer, target: EGFR)
* Antivirals (i.e. resistance based on form of HIV)
* Tarceva (lung cancer, target: EGFR)
* Strattera (ADHD, Metabolism: P4502D6)
95
Prenatal Diagnosis
•testing a fetus known to be at risk
96
Prenatal screening
testing for certain common birth defects (chromosomal aneuploidies, NTD) in pregnancies not known to be at increased risk for a birth defect or genetic disorder
97
birth defects affect ____ of births in US each year
1/33
98
Laboratory evaluation of the mother and fetus
99
most common reasons for prenatal genetic dx (8)
1. mom \>35 @ date of delivery
2. previous child with chr abnorm/genetic disorder
3. parent is carrier of balanced txloc or other struc chr disorder
4. parent is carrier of monogenic (mendelian) disorder
5. both parents carriers of auto-recess
6. mom carrier of sex-linked disease
7. congenital anomaly on 1st trimester ultrasound exam
8. abnormal aneuploidy screen (cell free DNA)
100
Ultrasonography
non-invasive
detect structural fetal anomalies
* single dene
* multifactoral
* specific struc syndromes
multiple fetal abnormal increase likelihood of CHR abnorm fetus
101
Sonogram Markers Suspicious for Down Syndrome
102
chorionic villus sampling (CVS)
**invasive**
* catheter/needle insertion into placenta and aspirate choironic villi from trophoblast
10-13 weeks gestation
assess fetal karyotype (7-10 days)
•Risk of pregnancy loss similar to amnio with transabdominal approach
103
limitations of CVS
no amniotic fluid collected so NTDs cannot be assessed
1% samples are ambiguous does to chr mosaicism --\> req f/u amnio
104
Amniocentesis
Invasive
* 20-22g Spinal Needle inserted transabdominally into the amniotic sac to obtain amniotic fluid
15-20 weeks gestation under ultrasound guidance
dx fetal aneuploidy and amniotic fluid
* alpha fetoprotein
* cytogenetics (karyotype, FISH)
* genome analysis
* enz meas
* fetal lung maturity
* bilirubin concentration
* PCR for pathogens
105
Amniocentesis Risks
incr risk of preg loss
AF leakage
infection
injury to fetus
106
Fetal Blood Sampling
•cordocentesis or percutaneous umbilical blood sampling (PUBS)
INVASIVE
* 20 wks
rapid fetal karyotyping: 24-48 hrs
* blood type
* genetic/chr abnorm
* fetal infections
* fetal anemia/thrombocytopenia
107
```
Preimplantation
Genetic Diagnosis (PGD)
```
testing of embryos during IVF:
* FISH
* PCR
* CMA: chr microarray analysis
allows couples @ high-risk for genetic disorder in their offspring to avoid preg term
types:
* blastomere: single cell removed 3 days after IVF when emb is 8-16 cells
* blastocyt: 5 trophoectoderm cells removed 5-6 days after IVF when blastocyst dev
108
conventional karyotyping turnaround time and conditions detected
7-14 days
chr abnorm
109
FISH: turnaround time, conditions detected
24-48 hours --\> 7-10 days
rapid assessment for chr: 13, 18, 21, X, Y
* early stage
* direct testing less accurate than cultured cells
110
PGD: turnaround time, conditions detected
preimplantation genetic diagnosis: IVF
1-2 days
genetic dx when fam mut ID'd
* potential error and needs confirmation
111
Cell-Free fetal DNA (cfDNA) screening
Noninvasive prenatal screening (NIPS), **highly accurate**
* comon auto and sex chr aneuploidies
* RISK ASSESSMENT: abnorm needs f/u with invasive dx to confirm results
\> 7+ wks gestation, MS contains free fetal DNA derived from placental trophoblasts
* Preferred \>10weeks to ensure adequate fetal fraction (3-4% of total maternal cfDNA)
cfDNA isolation followed by high-throughput sequencing
112
indications for cfDNA screening
\> 35 y/o
high risk of trisomy's
abnorm ultrasound findings
abnormal screening tests
113
Limitations of cfDNA Testing (6)
1. high cost, time consuming
2. cannot detect polyploidies or single gene disorders
3. diff to detect mosaicism cases
4. SCREENING ONLY: positive test needs confirm by invasive
5. canot predict preg complications
6. needs informed consent
114
for hte dx of specific diseases in which the genetic basis is known, use...
PCR
CMA
115
for aneuploidy detection, use...
cytogenetic analysis
FISH
116
for massively parallel seq, use...
cfDNA
117
cytogenetic analysis
any tissue with cells capable of dividing
conveitional g-banding of metaphase --\> aneuploidys, lg struc changes
limitations:
* cultured cells
* does not ID microscopic gene defects
118
FISH
rapid method of screening fetal cells for common aneuloidies
* loc presence/absence of specific DNA seq
no culture: 1-2 days on interphase nuclei
lim:
* ONLY on chr/gene of interest: 13, 18, 21, X, Y
* if abnormal --\> req confirmatory since it is NOT DIAGNOSTIC
119
Chromosomal Microarray Analysis
HIGH RESOLUTION (more infor than conventional KT)
* ID chr aneu and lesions too small to be detected by KT
no culture
ACOG guidelines: use CMA when structual abnorm detected on ultrasound
lim:
* cannot detected BALANCED rearrag
* low lvl mosaicism
120
neural tube defects
2nd more common ceongenital anomal worldwide
failure of neural to close by **27th day** after conception
* anecephaly
* encephlocele
* spina bifida
screen: MS alpha fetoprotein (MSAFP) @ 15-20 weeks gestation
121
Distribution of maternal serum α-fetoprotein (AFP) of unaffected and affected
122
Approaches to aneuploidy screening
•First-Trimester Screening (11-14 wks)
–US measurement of nuchal translucency (NT) and two MS analytes (β-hCG, PAPP-A)
•Second-Trimester Screening (15-20 wks)
–Quadruple screen (MSAFP, β-hCG, unconjugated estriol, inhibin A)
•Integrated screening
–Combined First- and Second- Trimester Screening
123
Elevation and Depression of Parameters Used in First- and Second- Trimester Screening Tests
* trisomy 21
* trisomy 18
* trisomy 13
* neural tube defect
124
1st trimester screening test
10-13 wks: 82-87%
* early single test
* lower detection rates, needs NT
method:
* NT +
* PAPP-A
* hCG
125
triple/quad screen
15-22 wks: 69-81%
* single test u/s not req, screens for NTD
* lower detection rates
method:
* hCG
* AFP
* uE3
* inhibin-A
126
cfDNA screening test
10wks - term: 99%
* highest detection rate possible, low false positives
* results do not always represent fetal DNA, still needs confirm testing
method: molecular
127
nuchal translucency
10-13.6 wk: 64-70%
* indiv fetal assessment in multiple gestations
* u/s certification needed
method: u/s only
128
groups with incr risks of sickle cell and method of inherit
african
mediterranan
middle east
indian
inherit: auto-recessive
129
groups with incr risk of alpha/beta-thalassemia and inherit pattern
african
mediterranean
middle east
west indian
SE asian
inherit: auto-recessive
130
groups with incr risk of CF and inherit pattern
non-hispanic white
ashkenazi jew
native american (zuni, pueblo)
inherit: auto-recess
131
groups with incr risk of inborn errors of metab and inherit pattern
ashkenazi jew
* tay-sachs = more common with fr-canadian and cajun
inherit: auto-recess
132
Copy Number Variations (CNVs)
human polymorphism = variation in the number of copies of segments of the genome ranging in size from 1000 bp to hundreds of kilobase pairs.
133
Multiple of the median (MoM)
expression of the comparison of MSAFP levels from pregnant women in the mid-trimester of pregnancy to median MSAFP values from women with normal fetuses at comparable gestational ages
134
Nuchal translucency (NT) measures
the thickness of the echo-free space between the skin and soft tissue over the dorsal aspect of the cervical spine
135
tx for genetic diseases may appear successful but long-term may....
subtle inadequacies:
* diff to maint diet restrictions (PKU)
adverse side effects:
* iron overload from freq blood txfusions (thalassemais) --\> req iron-chelating agents (deferoxamine)
136
non-classic PKU
mutations in BH4 (tetrahydrobiopterin) metab
137
allelicc heterogenetiy in PKU
\>500 mutations ID'd
138
Kuvan
sapropterin HCL
tx: PKU
139
tx for ornithine transcarbamoylase deficiency
1. restrict proteins
2. supplement with citrulline
3. ravicti: Glycerol phenylbutyrate
4. buphenyl: Sodium phenylbutyrate
5. ammonul: Sodium benzoate, sodium phenyl-acetate
140
tx lesch-nyhan syndrome
xanthine oxidase inhib: allopurinal (zyloprim)
141
tx FH (fam hypercholes)
1. statins: vastins: lipitor, crestor
2. BA sequestrants
3. use aphresis to remove LDL from circ
142
tx marfan
losartan (cozaar): ATII receptor antagonist
* •Angiotensin II signaling known to increase TGF-b activity
decr rate of aiotic root dilatation when added to standard beta blocker tx
143
examples of BA sequestrants
Cholestyramine
Colestipol
144
ataluran
tx: CR, DMD
small molecule thrapy to allow skipping over nonsense codons
145
tx hemophilia A and B
protein augment - protein/aa replacement
* A: fac VIII
* fac IX
146
tx gaucher
protein aug: Beta-glucocerebrosidase
147
tx pompe disease
protein augment: •Alpha-glucosidase (Lumizyme)
148
tx fabry disease
protein aug: •Alpha-galactosidase (Fabrazyme)
149
tx ADA deficient SCID
protein aug: adenosine deaminase (ADA)
150
hurler syndrome: MPS I
protein aug: •Laronidase (Aldurazyme)
* polymorphic variant of a-L-iduronidase
151
tx Hunter Synd., MPS II
protein aug: •Idursulfase (Elaprase)
* purified form of iduronate-2-sulfatase
152
tx sickle cell
INCR gene expr from locus not affected by disease
hydroxyurea
* release NO
decitabine: incr HbF lvls
* DNA hypomethylation
153
tx DMD
eteplirsen: antisense oligont (AON) targeting exon 51 - exon skipping
154
stem cell txplant
adult stem cells (pluripotent) - i(induced)PSCs
emb stem cells (totipotent) - hESCs
* derived from inner cell mass
155
How are hematopoietic stem cells and mesenchymal stromal cells harvested?
Bone marrow contains hematopoietic stem cells & mesenchymal stromal cells
156
\_\_\_\_\_\_\_can also be a source of hematopoietic stem cells and mesenchymal stromal cells
adv versus disadv?
Umbilical cord blood
adv:
* faster avail
* 1-2 HLA mismatches out of 6 tolerated
* lower incidence and severity of actue graft versus host
disadv:
* lower # HSC
157
iPSCs are derived from
somatic cells
direct reprogramming using Ts:
* Oct4
* SOX2
* c-MYC
* KLF4
158
examples of genetic disorders that use SCT
hered blood disorders: sickle, thalass
LSD: MPS, mucolipiodses
luek/lymphomas
SCID
osteogenesis imperfecta
159
Gene therapy for SCID due to ADA deficiency
use retrovirus as vector:
other options:
* BMT
* RBC txfusions
* ERT
160
gene editing
allows insertion/deletion/alt of DNA @ specific site in genome
poss of PERM curing disease
CRISPR-Cas9
161
tx CF
small molecule therapy
ivacaftor: potentiator to INCR Cl- gates
* incr fx of correctly trafficked mutant membrance proteins
lumacaftor: improve intracell trafficking of deltaF508
* correct folding of mutant membrane proteins
orkambi: lumacaftor-ivancaftor
* correct folding of mutant membrane proteins
162
tx hereditary transthyretin-mediated amyloidosis
RNAi
* Patisiran (RNAi IV targetting transthyretin)
partial mod by liver txplant
163
what are diseases "tx" by liver txplant?
hered transthyretin-med amyloidosis
urea cycle defects
acute intermittant prophyria
GSD I, III, IV
164
generated mouse model for sickle cell tx is tx by
iPSC
165
1st human clinical trial for Stargardt disease/AMD tx
emb stem cell
* txplant
* retinal pigment epithellium
166
what genetic disorders use adenoviral vector as tx?
hemophilia B (IV)
LPL deficiency (IM)
167
what diseases are tx using lentiviral vector
autologous HSC
* beta-thalassemia
* sickle cell
* x-linked ALD (adrenleukodystrophy)
168
indel
insertion or deletion generating a premature stop codon
169
give ____ for urea cycle defect
sodium benzoate
