BLD unit 3 Flashcards
(199 cards)
1
Q
name anatomy of blood vessel most superficial to deep
A
smooth muscle and ECM, luminal lining/endothelial layer, lumen (where blood is)
2
Q
use terminology superficial to deep of blood vessel
A
adventitia, media, intima
3
Q
describe arteries
A
large and elastic, medium and muscular, small
4
Q
what is the order of vascular organization
A
ateries, veins, capillaries, lymphatics
5
Q
where are pericytes
A
surround endothelial cells
6
Q
name the functions of the endothelium
A
thrombosis balance, smooth muscle behavior, modulate inflammation, influence growth of other cells, modulate vascular permeability, oxidize LDL
7
Q
describe endothelial cell activation
A
change shape to create gaps in BV, produce adhesion molecules (selectins and ICAM), produce cytokines and coagulation influencing factors
8
Q
list the inducers that activate the endothelial cells (inflammation)
A
bacteria and viruses, pro-inflammatory cytokines (TNF-alpha, IL-1), stress, lipids, complement, hypoxia (ischemia)
9
Q
what do vascular smooth muscle cells do
A
vasoconstrict and vasodilate, function in normal repair and pathology (atherosclerosis)
10
Q
unique role of smooth muscle cells
A
proliferation, up regulation of ECM components and release of growth factors and cytokines (communication)
11
Q
what regulators activate smooth muscle cells
A
PDGF, endothelin, thrombin, FGFs, IFN-gamma, IL-1
12
Q
what is FGF
A
fibroblast growth factors
13
Q
what is PDGF
A
platelet derivative growth factor
14
Q
what regulators keep smooth muscles BASAL
A
heparan sulfate, NO, TGF-alpha (NOT TNF-alpha)
15
Q
what pressure pushes down on BV
A
plasma colloid osmotic pressure
16
Q
what pressure pushes out of BV
A
hydrostatic pressure
17
Q
define hydrostatic pressure
A
the pressure that blood exerts on the vessel
18
Q
define plasma colloid osmotic pressure
A
the pressure exerted by different concentrations of molecules on the inside and outside of the vessel (flow of water because of solute concentration)
19
Q
define interstitial fluid pressure
A
pressure exerted by the fluid in the interstitial spaces outside the vessel (interstitial space)
20
Q
what causes fluid to LEAVE vasculature
A
1) increased intravascular hydrostatic pressure (increase blood pressure on the inside of BV) = leaky, 2) increased colloid osmotic pressure in the extravascular compartment ( outside of BV has increased solute conc. from loss of albumin, so fluid leave)
21
Q
what helps fluid STAY in BV
A
1) osmotic pressure of plasma proteins (albumin) 2) selective permeability of endothelium 3)tissue tension (tension around BV push INTO BV)
22
Q
normal net loss from the vasculature returns through what
A
lymph system
23
Q
define hematoma
A
bleeding in area
24
Q
hemothorax
A
bled into thoracic cavity
25
hemopericardium
bled into the pericardium
26
hemoperitoneum
bled into peritoneum
27
hemoarthritis
bled into joint
28
petechiae
smallest bruises, bleed under skin
29
purpura
bigger bruise, bleeds are more severe
30
ecchymoses
normal bruise
31
what are the 3 ways to judge a hemorrhage
volume, rate, general health of the patient
32
what are the 3 elements of hemostasis
vascular wall: endothelium, platelets, coagulation cascade
33
steps after bleed:
1) vasoconstriction 2) platelets (AAA) 3) coagulation cascade (thrombin) 4) thrombin (stable clot) 5) counter-regulation stops process
34
what does endothelin mediate
vasoconstriction
35
primary hemostasis:
platelet plug
36
secondary hemostasis:
coagulation cascade make fibrin
37
fibrinolysis does what
cleans up, cuts up clot and gets debris out, destroys net
38
platelet plug fills what
damage to the endothelial layer, exposes ECM
39
the platelet plug facilitates what
AAA (adherence, activation, and aggregation)
40
what is the initial platelet plug called
primary hemostasis
41
what is T-PA
tissue type plasminogen activator cleaves plasminogen to plasmin which then degrades fibrin
42
what does thrombomodulin do
halts the coagulation cascade
43
clot busting drugs do what
speed up fibrinolysis
44
what are the effects of PRO hemostasis (clot)
vWF activation, TF activation of coagulation cascade, plasminogen activator inhibitors (stop cutting up clots)
45
what are the effects of ANTI hemostasis (anti-clot)
inhibit platelet by hiding ECM, inhibits coagulation factors with HEPARIN like molecules thrombomodulin and TFPI, fibrinolysis (TTPA)
46
platelets contain
cell fragments containing:
alpha granules and dense bodies (store Ca2+)
integrins (adhesion)
cytoskeleton (need to change shape)
47
what stimulates platelet activation
granules release: Ca2+ (coagulation factors), ADP (platelet activator), TxA2 (activates more platelets, aggregation (AA metabolism)
48
during platelet aggregation fibrinogen binds to what
GPII/IIIa receptors to form bridges
49
during platelet aggregation thrombin does what
activates PAR and converts fibrinogen to fibrin (cuts it up)
50
what are the effects of thrombin
activates platelet aggregation and endothelial cells, generates fibrin, activates leukocytes
51
name some antithrombins
inhibit thrombin: IXa, Xa, XIa, XIIa
52
name some protein C and Protein S anticoagulation systems
vitimin K dependent, act on Va and VIIIa
53
What does the tissue factor pathway inhibitor in anticoagulation system do
inhibits entry into extrinsic coagulation pathway
54
define edema
abnormal accumulation of fluid outside the vasculature
55
what 2 factors causes fluid to leave the vasculature
1) increased intravascular hydrostatic pressure. 2)increased colloid osmotic pressure in the extravascular compartment
56
what 3 factors helps fluid remain in the vasculature
1) osmotic pressure of plasma proteins, especially albumin
2) the selective permeability of the endothelium
3) tissue tension
57
where does normal net loss from the vasculature through
lymph system
58
define transudate
edema due to increased hydrostatic pressure or reduced intravascular protein
59
define exudate
edema due to increased vascular permeability (inflammation)
60
4 most important factors for edema
1) increase in intracapillary pressure
2) decrease in plasma osmotic pressure
2a) lymphatic obstructions (block backflow)
2b) retention of salt/water
61
what are the 3 types of systemic edema
cardiac edema, renal edema, and chronic liver disease edema
62
what are the main components of cardiac edema
redistribution and retention of fluids in areas within the body, gravity influences distribution,
63
what is cardiac edema caused from
weak pumping of the heart lead to increase in venous pressure
important: excessive retention of Na+ and H2O by the kidneys (kidneys will hold onto salt and water in response to this)
64
effects of cardiac edema
1) decrease renal blood flow due to faulty pumping (activates RAAS which increases retention of Na+ and H2O)
2) increase in blood volume and intracapillary hydrostatic pressure (makes BV leaky producing transudate)
65
what are the main components of renal edema
heavy proteinuria due to leaky capillaries (damage, inflammation)
- loss of albumin exceeds liver production
- decrease in plasma oncotic pressure leading to edema
66
what are the main components of chronic liver disease
- edema presents as ascites
causing:
- increase intracapillary pressure (from scarring in liver -> less flexible -> increase pressure)
- decrease in albumin/plasma oncotic pressure
- increase hepatic lymph (due to inflammation)
- increase in Na+ retention if cirrhotic
67
what are the 3 types of local edema
1) increased hydrostatic pressure in the microcirculation
2) increased local vascular permeability
3) lymphedema
68
define hyperemia
extra blood coming into the area, outflow remains the same (vasodilation)
69
define congestion
normal flow to area , blockage of outflow causing high volume of blood in area
70
define shock
clinical syndrome characterized by systemic underperfusion due to prolonged diminished cardiac output or reduction in blood volume
71
what are the 3 types of shock discussed
hypovolemic, cardiogenic, septic shock
72
what are the main components of hypovolemic shock
decrease blood/plasma volume
causes: severe hemorrhage (bled out)
major loss of body fluids (dehydration event)
severe burns (decrease volume)
73
what are the main components of cardiogenic shock
decrease cardiac output
- could be due to MI, occlusion, arrhythmia *anything that significantly reduces hearts ability to pump*
74
what are the main components of septic shock
(excessive inflammatory response) systemic immune response to microbial infection, results in arterial vasodilation, increased vascular permeability (inflammation), and venous pooling
75
what are the underlying factors that lead to septic shock
PAMPS -> activation of cells -> TNF and IL-1 -> ROS, AA metabolites, complement (all amplify the inflammatory response)
76
what are the main components of superantigens
toxic shock syndrome
- activate t cells which produce large amounts of cytokine and causes giant inflammatory response that shouldn't be there
77
what are the other 2 ways to classify shock:
destributive vs obstructive
78
describe distributive shock
due to problems getting blood around in the body, not enough to fill the vasculature
79
describe obstructive shock
due to problems with the heart filling or blockages near the heart. due to obstruction, the blood is not going out to the body properly even though there may be enough
80
what are the 3 stages of shock
non progressive, progressive, and irreversible
81
wait is the main trait about non progressive shock
body can accommodate the blood loss, organ perfusion maintained
82
what are the main traits with progressive stage shock
hypoperfusion, metabolic problems, acidosis
83
what is the main trait with irreversible stage shock
severe injury
84
what are symptoms of non progressive stage shock
tachycardia, vasoconstriction, renal fluid conservation
85
what are the symptoms to progressive stage shock
low oxygen available to tissues and organs, increased levels of lactic acid due to anaerobic glycolysis, blood pooling and risk to endothelium
86
what are the symptoms to irreversible stage shock
widespread cell injury, cardiac pumping weakens, septic shock addition, and kidney failure
87
define thrombosis
problem when clotting is in the wrong place at the wrong time
88
define hemostasis
results in the NORMAL formation of clots when required and fibrinolysis removes them when ready
89
Define Virchow's triad (what promotes thrombosis)
changes in the intima of vessel
changes in the pattern of blood flow
changes in the constituents of the blood
90
define injury to vessel
anything that removes or changes the endothelium:
exposes the ECM beneath which activates platelets, changes in the coagulation influence, chronic inflammation
91
what are the Pro-coagulative cells effects
vWF activation of platelets, TF activation of coagulation cascade, plasminogen activator inhibitors
92
what are the Anti-coagulative cells effects
inhibit platelets by hiding ECM, inhibits coagulation factors with heparin like molecules, thrombomodulin, and TFPI, and fibrinolysis (T-PA)
93
how can turbulence change the pattern of blood flow
(roughness of flow) which can activate endothelium and cause pooling
94
what are some causes of stasis in heart and large vessels
aneurysms, congestive cardiomyopathy, MI, mitral valve problems
95
how do changes in blood content cause a hypercoagulative state?
changes increase risk for VENOUS thrombosis (can cause primary or secondary hypercoagulation)
96
what are the risk factors for hypercoagulable states?
more procoagulant factors like fibrinogen, decrease in those natural anticoagulants?
97
What are the common inherited disorders with risk of thrombosis
Factor V-Leiden mutation and Prothrombin mutation
98
Describe Factor V-Leiden mutation
affects the coagulation cascade, promotes clotting, activated factor Va never gets destroyed which increases activity
99
describe Prothrombin mutation
promotes clotting by high levels of prothrombin expression (too much of a good thing) and prothrombin becomes thrombin
100
what are the rare inherited disorders with risk of thrombosis
1) antithrombin III
- recurrent episodes of venous thrombosis
2) Protein C deficiency/resistance
- either decreased amounts or functional defect with normal amounts or missing cofactor that helps with protein C
3) Fibrinolytic pathway disorders
- cannot break down clots
101
what are some other risk factors for thrombosis
oral contraceptives (estrogen levels) which increase fibrinogen and Vitamin K, but decreases Antithrombin III
( promotes clotting factors but decreases breaking down clots)
102
what is another risk factor for thrombosis
malignancy:
-mucin releasing tumors can activate Factor X
- some tumors release proteases which also activate Factor X
103
what are some immune risk syndromes for thrombosis
HIT syndrome and Antiphospholipid antibody syndrome
104
describe HIT syndrome and how it relates to thrombosis
patients treated with heparin (anticoagulant) which makes autoantibodies bind heparin and platelet membranes = chronic inflammation
105
describe antiphospholipid antibody syndrome and how it relates to thrombosis
complex syndrome that results in autoantibodies that cause endothelial injury, platelet activation, interaction with coagulation factors
106
what happens to thrombi?
-usually lysis due to plasmin
- propagate = clotting can lead to more clotting
- embolus = clot floats around until is reaches a vessel that is too narrow to pass (ischemia)
107
what are emboli's mainly composed of
thrombus (99%) and blood clots, air, nitrogen, fat, chunks of bone
108
describe pulmonary embolism
starts with DVT = most come from your knee pit, having one increases risk for another
109
describe the pathway for a pulmonary embolism
venous thrombus -> pulmonary arterial tree (lodge is in pulmonary arch) and blocks blood and oxygen to the lungs
110
the effects of pulmonary embolism depends on what two factors
1) size of embolus:
2) congestion in the pulmonary circulation
- excessive accumulation of fluid in the lungs
111
describe a massive pulmonary emboli
- 5% of cases
- from a long segment of a vein in the leg
- has to be big enough to block the pulmonary arteries which are bigger than most veins
112
what is the clinical presentation of a massive pulmonary emboli
sudden, SOB and CP, acute right sided heart failure, shock
113
describe a medium pulmonary embolism
(10-15%)
- some degree of circulatory obstruction leads to localized rupture of capillaries and hemorrhage
- major symptoms = DYSPNEA
114
describe a small pulmonary emboli
(60-80%)
- clinically silent
- too small to cause a problem
- fibrinolytic system breaks it down while the bronchial circulation keeps the lung tissue supplied with oxygen
115
describe systemic emboli
- thromboembolism is most common
- major source: left side of the heart
causes:
- atrial fibrillation
- MI
- congestive cardiomyopathy
- infective endocarditis
116
where can a systemic emboli be seen
wherever the emboli gets lodged, most often:
- spleen, kidney, brain, legs, GI tract
117
Rarer types of embolisms include
amniotic fluid, gaseous (air),
118
describe amniotic fluid embolism
(80% mortality rate)
- amniotic fluid enters blood of the mother
- caused by a traumatic birth
- uterine vein is torn
- ends with possible DIC
119
describe DIC
Disseminated intravascular coagulation:
- multiple small clots throughout the vascular system
- uses up coagulation resources so may lead to bleeding
120
describe gaseous emboli (air)
introduced to circulation by:
- surgery
- chest surgery
- fallopian tubes in exploration of sterility
121
what is the mechanism for air emboli
- air enters the right side of the heart, making frothy mess that can block blood fow
- similar to massive pulmonary embolism (clincally)
- froth may mobe out into circulation and cause problems at other sites like the brain and spinal cord
- 40 mL can cause problems, 100 mL usually fatal
122
describe gaseous embolism (nitrogen)
- decompression sickness,
- divers returning to normal atmospheric pressure from high pressure too quickly
- high pressure N2 dissolves in plasma and tissue
- as pressure decreases, N2 comes out of solution and forms bubbles (N2 emboli)
123
what are the clinical symptoms of nitrogen emboli
- bubbles can be in circulation or tissue
- symptoms include: pain "the bends", respiratory distress, CNS problems, ischemic damage to long bones
124
Fat embolism
seen in 90% of patients with severe skeletal trauma, but only 10% show symptoms
Sources:
- fracture of long bones
- severe burns
- severe soft tissue trauma (crushing)
125
mechanism of Fat embolism
- bone-marrow derived fat globules enter veins and lodge in the pulmonary vasculature
- may also trigger platelet aggregation
- 7-10 micrometers can pass through capillaries there
126
what is the clinical presentation of fat embolism
- anemia, thrombocytopenia, petechial rash, pulmonary dysfunction
127
define ischemia
blood flow less than the tissue metabolism requires
128
define infart
happens when ischemia happens too long, localized necrosis in area
129
define hypoxia
decreased concentration of oxygen
130
why do we car about infarction?
#1 cause of death in adults, most deaths are due to myocardial or cerebral infarcts
131
examples of blockages causing ischemia
"twisted bowel", strangulated hernias, frostbite
132
factors that influence infartion?
alternative blood supplies to area, how fast the blockage occurs, how vulnerable is the tissue without blood, what are the blood oxygen levels like
133
symptoms of ischemia (function)
pain upon exertion
- eventual cellular damage leads to more functional loss
134
symptoms of ischemia (structure)
- necrosis results (patchy or massive)
- fibrous tissue when healed
- degree of necrosis is proportional to degree of ischemia
135
describe cardial infarcts
- different clinical pictures
- "stable" angina - only upon effort
- "unstable" angina - at rest
- sudden death: left ventricle arrhythmia (acute MI, failure of pumping due to loss of muscle)
136
describe the complications of cardiac infarction
early: arrhythmia and sudden death
Necrosis: softening and rupture or valve problems
ventricular problems can lead to thrombosis
healing: fibrous tissue leads to pumping deficiency or even aneurysm
137
describe intestinal infarction (bad)
many causes:
- emboli/thrombi in mesentery veins/arteries
- most mechanical: hernial strangulation, twisting, intussusception (bowels roll up)
138
what are the symptoms if intestinal infart
stiff, dark color, fibrous inflammation on interior surface, gangrene (from microbiota)
139
define how injury leads to arteriosclerosis
"hardening of the arteries" and thickening due to collagen build up, loss elastic nature
140
what are the 3 types of arteriosclerosis
- arteriolosclerosis
- Monckeberg medial sclerosis
- atherosclerosis (most common)
141
what is first seen with arteriosclerosis
fatty streaks:
- earliest
- small lipid rich yellow dots
- starts in infants
- mild thickening due to more intimal cells
- DOES NOT HAVE TO PROGRESS
142
what is seen next in arteriosclerosis
atherosclerosis:
- happens in large elastic muscular arteries
- lesions: thickenings of the innermost layers of arteries (tunica intima) partly lipid and partly connective tissue
143
what is seen within an atherosclerotic core
lipids contained within foam cells or in pools, collagen, Ca2+ deposits
144
what is step 1 in response to injury hypothesis
chronic endothelial injury:
- dysfunction of endothelial cells
- more permeable
- WBC's adhere more easily
- gene expression changes
- thrombosis
145
step 2:
accumulation of lipoproteins
- oxidized LDL and cholesterol crystals build up in the vessel wall
146
step 3:
platelet adhesion:
- platelet are attracted to the damage
147
step 4:
monocytes get involved and migrate to intima
148
step 5:
lipid accumulation in macrophages (foam cells)
- causes release of inflammatory cytokines
- more ROS production drives LDL oxidation
- GF production stimulates smooth muscle proliferation
149
step 6:
smooth muscle recruitment from media
- smooth muscle cells proliferate an release ECM building the cap
150
Describe plaques and how they cause problems
location matters, raised plaque is where problems develop, structure of atheroma and its placement in the vessel matters
- thin caps with large lipid cores are more of a risk
151
characteristics of vulnerable plaques
-large lipid cores
- thin caps with few SM cells
- lots of inflammatory cells
152
why test cholesterol levels:
HDL decreases risk since it carries fat away from cells for storage
- LDL increases risk since it brings fat to cells for energy
153
describe the human genome
23 pairs of chromosomes (22 autosomal, 1 pair sex chromosomes)
154
what are the jobs of non-protein coding genes
- promoters and enhancers
- chromatin scaffolding
- non-coding RNA
- mobile genetic elements
- special structures like centromere and telomeres
155
describe types of human variation within the genome
single nucleotide polymorphism (SNP):
- one letter change in DNA
- can affect phenotype or be neutral
-neutral can be used for ID
Copy number variation (CNV):
- different numbers of copies of long stretches of DNA
- duplications, deletions of copies
- inversions where things get switched around
- 50% are in gene-coding regions = do affect phenotype
156
describe genotype and phenotype
genotype: DNA code
phenotype: observable outcome of DNA code
157
define congenital, familial, and heriditary
congenital: present at birth
familial: appears to be passed on in a family where mutation is known or unknown
hereditary: transmitted in the parental gametes
158
what are common markers for epigenetic regulation
DNA methylation (silencing), histone modification
- these affect availability of the genome for transcription
159
define mutation
permanent change in the DNA code:
outcomes can be:
- positive trait (resistance to disease)
- deleterious trait (loss of function of enzyme)
- neutral (no change)
160
what are the two types of mutation in human disease
somatic:
- only affects the person with the mutation
Germline:
- may be passed onto offspring via gametes
161
types of DNA mutations:
amplification:
- extra copies of a gene or length of DNA
deletions:
- loss of a gene or one copy of a gene
translocations:
- switching of selection of DNA between two chromosomes
162
describe the genetic disease mendelian disease:
from mutations in a single gene
163
describe the genetic disease complex of multifactorial disorders:
multiple genes involved in environmental influences too
164
describe the genetic disease cytogenic disorders:
arising from chromosomal number or structural differences
165
describe mendelian inheritance patters
can be autosomal or sex linked (usually X-linked)
AND
dominant or recessive
166
describe autosomal dominant mendelian disorders
- heterozygotes manifest this disorder
- one parent usually affects
- same frequency in gender
- autosomal
- 50% loss of protein production from gene (regulatory molecules or structural protein genes not enzymes)
167
define penetrance and variable expressivity
penetrance: probability that a mutant allele will be expressed phenotypically (expressed/possessed)
Expressivity: severity of expression of phenotype
Variable expressivity: different mutations in the same allele can have varying effects in severity
168
Autosomal dominant: Ehlers Danlos Syndrome ( EDS)
group of disease (not all dominant) - characterized by deletion mutation in collagen synthesis or structure
clinical presentation:
- skin, ligaments, and joints are most affected, skin fragility is common, hyperflexibility of skin and ligaments
- serious internal complications with organs and vasculature
169
EDS 2 types of mutations in most common variants
- COL3A1 gene: deficient type III collagen predisposes blood vessels to rupture
- COL5A1 and COL5A2: deficient type V collagen production creates classical EDS presentation
170
autosomal dominant: familial hypercholesterolemia
loss of function LDL receptor gene mutation results in abnormal levels of LDL in blood (cannot take fat in as energy)
clinical presentation:
- heterozygotes have 2-3x increase in blood LDL, homozygotes have 5X (worse)
- elevated cholesterol from birth, problems in adulthood
- xanthomas on skin and tendons PREMATURE ATHEROSCLEROSIS
171
Familial hypercholesterolemia continued
mutation in FH general reduces LDL receptor expression or endocytosis (take in receptor into cell)
other cases:
- LOF in ApoB which helps LDL bind to the receptor
- gain of mutation in PCSK9 which reduces the expression of LDL receptor in liver cells so the liver can play role in fat metabolism
172
characteristics of autosomal recessive disorders
- only manifest in homozygous state when both alleles are mutated
- don't see trait in parents usually but they are both carriers
- 1/4 chance of siblings being affected
- if mutation has low frequency in the population, parents may be related
- largest group of genetic disorders
- expression is consistent and similar to parents
- complete penetrance
- early onset
- usually enzymes are encoded in affected genes
173
Autosomal recessive: cystic fibrosis
disorder of epithelial ion transport (affects fluid secretion in exocrine glands and lining of respiratory tract, GI tract, and reproductive tract)
clinical presentation:
- recurrent, chronic lung infections
- pancreatic insufficiency (fecal loss of protein and fat)
- high NaCl in sweat
-variance in mutation = variance expressivity
174
CF continued
mutations in CFTR cause CF
Most common cause: deltaF508/detlaF508 (loss of phenylalanine)
causes of mutation:
1) do not make CFTR
2) CFTR processing/trafficking to surface defective
3) defective CFTR regulation
4) conductance in CFTR defective
4) CFTR stability in membrane defective
175
autosomal recessive: phenylketonuria (PKU)
mutations cause a severe lack of enzyme that causes an increase in plasma PA. enzyme is PAH (phenylalanine hydroxylase)
clinical presentation:
- early weeks of life see climbing P levels
- musty/mousy odor of urine and sweat
- impairs brain development
- if not treated by removing P from diet, severe mental disability by 6 months
176
PKU methodology
problem is the inability to convert PA to Tyrosine, usually about 50% from diet because of lack of PAH
177
autosomal recessive lysosomal storage disease: Tay-Sachs
one of a group diseases that stems from problems at the lysosome, very rare
clinical presentation:
- infant or very young
- blindness
- hepatosplenomegaly
waste products in brain accumulate bc the enzyme to break them down is missing (hexokinase)
178
Tay-Sachs continued
mutation in the hexosaminidase A alpha-subunit cause more common version of disease
- enzyme breaks down gangliosides in cells. when its target GMS accumulates instead the damage is significant in the brain and retina
179
Sex-linked disorder characteristics
Y-linked disorders are usually related to male infertility so we dont see them because they cannot be massed down
- X-linked:
- transmission is usually from females who are heterozygous carries whose hemizygous sons are affected
- female carriers are usually protected from symptoms by second normal X
- affected males do not pass disease to sons but all daughters are carriers
180
X-linked examples
-hemophilia A: coagulation factor VIII deficiency
- Duchenne/Becker muscular dystrophy: dystrophin gene mutations
- fragile X syndrome: amplified repeats disrupt developmental gene function
181
describe complex multigenic disorders
- dance between genetics and environmental factors can create disease
- can be the effect of multiple low penetrance polymorphisms in one genome
182
examples of multigenic effects on phenotype
hair color, skin color, height, type 1 diabetes
type 2 diabetes
183
cytogenetic disorders
- chromosomal abnormalities are likely present in 1:200 live births
- much higher in spontaneous abortions in first trimester
- Detect with karyotyping and FISH
184
Describe Karyotype
human normal diploid number is 46, 22 autosomal 1 sex pair
- any variation of this number can induce disorders = aneuploid
- usually number differences occur because of nondisjunction during meiosis
-mosaicism is when 2 or more populations of cells exist together with genomic differences (bone marrow transplant)
185
nondysjunction
abnormal number of chromosomes, can happen in meiosis 1 and 2
186
general features of chromosomal disorders
- absence, excess, or rearrangements of chromosomes
- less is worse than too many
- sex chromosome imbalances are tolerated better than autosomal
- most are de novo and not inherited except down syndrome
187
autosomal disorders: Trisomy 21 (down syndrome)
patients have an extra copy of chromosome 21
presentation:
- flat facial profile, distinct eye folds, palmar folds
- intellectual disability
causes:
- meiotic nondisjunction >95%
- maternal age (MA) is a big factor (Ovum)
excess of several genes implicated: beta amyloid precursor, microRNAs and IncRNAs
188
sex chromosome disorders
more room for variation:
- Y chromosome has small amount of genetic information so extra isn't a problem
- lyonization of X chromosome: part of X is turned off (XIST gene for IncRNA is invovled)
189
sex chromosome disorders: Klinefelter syndrome
at least 2 X and one or more Y chromosomes in a male individual (XXY)
presentation:
- hypogonadism
- elongated body
- lack of body hair
- gynecomastia (breast tissue development)
- infertility
190
sex chromosome disorder: Turner syndrome
primary hypogonadism in a phenotypical female resulting from complete monosomy of X or partial
presentation:
- below 3rd percentile in height
- swelling of nape of neck in infancy and webbing later
- widely spaced nipples
-low back hairline
191
define triplet repeat mutations
the overcopying of a specific set of 3 nucleotides within the gene disrupts its function
192
Fragile X syndrome:
CFF repeat expansion:
- CGG repeat in FMR1 gene on X chromosome leads to clinical symptoms
presentation:
- intellectual disability
- macroorchidism (enlarged testes)
- distinct facial features
193
Fragile X syndrome methods
average number of repeats in unaffected genome = 30
premutation: 60-200 copies
disease: 200-250 copies
(only females can accumulate more mutations)
194
define premutation level in Fragile X
initial change in the genome needs processing through female meiosis before it is fully expressed
- repeats increase due to "confused" DNA polymerase during replication. it loses its place and starts over and adds more CGGS
195
mitochondrial disorders
mtDNA is circular, several copies per cell, contains genes for ETC, 2 rRNA for making ribosomes
196
Mitochondrial disorders methods
mitochondria and maternal inheritance because ova has abundant cytoplasm mitochondria while sperm has few if any
197
explain why Mitochondrial disorders have higher rates of mutation
constantly exposed to ROS from the ETC = increases rate of mutation
- effect the energetics of the cell, especially in cells that need a lot of ATP
198
imprinting = Prader-Willi vs Angelman syndrome
imprinting method: methylation of gene promoter and modification of histones
199
Prader-Willi vs Angelman syndrome
PW:
- deletion is paternal
- imprinting (silencing) is maternal
A:
- maternal deletion
- imprinting is paternal
