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SBL Midterm > Biochemistry/Genetics > Flashcards

Biochemistry/Genetics Flashcards

1
Q

TQ

  • megaloblastic macrocytic anemias are the result of what?
  • what 2 substances are necessary for synthesis of DNA precursors?
A
  • abnormal (retarded) DNA synthesis in the bone marrow (can’t make RBC) and a nuclear maturation defect
  • B12 and folate
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2
Q

What happens if RBC are unable to mature in the bone marrow?

A

-RBC stay stuck in the bone marrow trying to mature and lead to megaloblastic macrocytic anemia!!

(cannot replenish red cell pop.)

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3
Q

Macrocytic anemia is characterized by large erythrocytes with MCV greater than 100. However, they have normal ________ in relation to size (normal MCHC)

A

hemoglobin

normochromic oval macrocytes on blood smear

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4
Q

Pt presents with…dx?

  • lethargy
  • weakness
  • yellow/waxy pallor
  • loss of weight & appetite
  • Diarrhea
A

Megaloblastic Macrocytic Anemia

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5
Q

On a blood smear you see large erythroblasts and hypersegmented neutrophils (more than 5 lobes)…dx?

A

Megaloblastic Macrocytic Anemia

decreased mitotic divisions, delayed nuclear development, expanding cytoplasmic volume

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6
Q

What neurological symptom presents with megaloblastic macrocytic anemia?

A

Peripheral neuropathy:

  • pins and needles
  • loss of ambulation
  • loss of memory
  • madness
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7
Q

TQ: What are the three parts of folic acid (pteroylglutamic acid)?

A
  • **Pteridine
  • PABA ring
  • Glutamic aa residues
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8
Q

Folate can exist as dietary folic acid (DHF: dihydrofolate) or THF (tetrahydrofolate). DHF is reduced to THF on the pteridine ring by what enzyme?

A

Dihydrofolate reductase

2H to 4H

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9
Q

What is the function of tetrahydrofolate (THF)?

A

Transfer carbon units (CH3) for DNA synthesis!

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10
Q

THF becomes a one carbon donor for synthesis of nucleotides by grabbing onto a methylene (CH2) group with its 2 nitrogens to become what?

A

N5, N10-methylene-FH4

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11
Q

Fill in the sequence of the folic acid pathway:
DHF–> (DHF reductase)
THF–>(gets CH2 from ______)
N5, N10-methylene THF–> (gives methyl to dUMP to form dTMP to form DNA)
Dihydrofolate

A

serine

Leads to DNA synthesis hence if folate issue then have anemia

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12
Q

What is the most common cause of folate deficiency? Who suffers most from this?

A
  • Inadequate dietary intake
  • Usually the poor and elderly due to junk food
  • alcoholics too!
    (others: GI dz, incr requirement in pregnancy, drug interference)
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13
Q

The recommended daily allowance is 200 ug of folate, __ ug minimum!

  • 50-80% absorbed in small intestine
  • Liver stores 5 to 10 mg for 3-6 mo
A

50

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14
Q

Why cant the folic acid pathway go on forever?

A

DHF is absorbed and reduced to N5-methyl-THF, which will NOT give up the single methylene group to dUMP–>dTMP for DNA synthesis!…must de-methylate using vit B12 for it to become THF!

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15
Q

TQ: What is the folate trap?

A
  • When B12 is not available then folate becomes trapped in N5-methyl-THF form
  • Therefore you have lots of folate but cant use it!!!
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16
Q

TQ: Vitamin B12 removes the methyl group from N5-methyl-THF to make methyl-cobalamin (B12-CH3), releasing THF to make DNA. What does cobalamin do with the methyl group?

A

Transfers it to homocysteine to create methionine via methionine synthase

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17
Q

Megaloblastic Macrocytic Anemia can also be caused by vit B12 deficiency, leading to a decrease of N5,10-methylene-THF and decreased DNA synthesis. Where can we find B12?

A

microorganisms! (cows tummy)

THEREFORE, rare to be deficient by diet!

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18
Q

Where do 85% of B12 deficiency come from?

A

lack of intrinsic factor!

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19
Q

Dietary B12 binds to proteins made by gastric mucosa cells called _-______ protein. Parietal cells make intrinsic factor nearby. Later on, the pancreas releases proteases to remove the protein and allow the intrinsic factor to bind B12 and carry it to the ileum for absorption.

A

R-binder proteins

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20
Q

Intrinsic factor-cobalamin binds to receptor cubulin, and is taken up via receptor-mediated endocytosis. B12 is carried throughout the blood by ________.

A

transcobalamin

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21
Q

What is it called when vit B12 deficiency occurs due to lack of intrinsic factor (needed for absorption)?

A

Pernicious anemia
-gastric mucosa destroyed due to auto-immune mech so no IF
(a megaloblastic macrocytic anemia)

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22
Q

What is the gold standard for diagnosing pernicious anemia?

A

Schilling test:

  • Give and unlabeled B12 and radioactive labeled B12
  • Unlabeled will bind all receptors available
  • Labeled will be absorbed and excreted in the urine (if no absorption issue)
  • Urine collected for 24 hours: if absent then anemic if not then diet issue!
  • If absent….repeat but ADD intrinsic factor…if this time the radioactive B12 present, then we know its the lack of intrinsic factor
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23
Q

How do we treat folate deficiency? B12 deficiency?

A
  • Folate: diet!
  • Pernicious anemia B12 injections for life!

(B12 def can also be cause by stomach removal and Crohn’s)

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24
Q

Total body iron is 3-5 g and 2.7g is in red blood cells. Each day we need 25 mg of Fe to support Hb production. Therefore, what must we do with iron?

A

Recycle it! The iron cycle

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25
Q

TQ

Does the body have a way to excrete iron?

A

NO!! NO iron excretion pathway

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26
Q

What is the iron cycle?

A 
Iron is absorbed into the gut then...
Plasma transferrin ion-->
Marrow erythroid precursors-->
Circulating erythrocytes-->
Macrophages-->
Back to plasma!

(CLOSED cycle, no excretion)

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27
Q

Where is the majority of iron in the body?

A

67% in hemoglobin!

27% stored as ferritin or hemosiderin-insoluble

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28
Q

Iron exists in two forms…what are they? In order to maintain solubility and limit toxicity, what must be done to iron?

A

2+ form=ferrous
3+ form=ferric

Iron chelated to proteins or molecules to maintain solubility and limit toxicity

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29
Q

TQ:
-Ferritin, an intracellular protein, binds thousands of Fe3+ molecules and is found in most cells.
-Hemosiderin binds granules of ferritin.
Where is the excess iron stored? (3)

A

Liver
Lungs
Pancreas

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30
Q 
Overall iron transport mechanism:
Dietary iron absorbed by DMT1
into enterocyte-->
Enterocyte to blood by \_\_\_\_\_\_\_-->
Transferrin to TfR on erythroblast-->
DMT1 to mitochondria to make heme
A

Ferroportin

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31
Q

Dietary ferric iron (Fe3+) is reduced to ferrous form (Fe2+) before being transported into enterocyte by DMT1. What enzyme reduces Fe3+?

A

DCYTB

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32
Q

Fe2+ iron is transported to the blood from the enterocyte by what enzyme? What is required to perform this transport?

A

Ferroportin transfers Fe to blood but first need to change Fe2+ to Fe3+ using Hephaestin!

(so that transferrin (prefers Fe3+) can later carry it to the bone marrow.)

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33
Q

In sex linked anemia mice, where is all the iron found?

A

In the intestine! Cant pump out of the enterocyte

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34
Q

Iron content in the body is regulated by modulating Fe absorption through what molecule?

A

Hepcidin (liver protein) acting on ferroportin (iron door)

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35
Q

What enzyme is used to transport iron through blood to bone marrow?

A

Transferrin

Binds 1-2 Fe3+ molecules with high affinity

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36
Q

TQ How does transferrin get iron into the erythroblast in the bone marrow?

A

Transferrin-Receptor (TfR) Mediated Endocytosis

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37
Q

TQ What are the overall steps of TfR Mediated Endocytosis (7)

A
  1. Transferrin+2 Fe binds to TfR and causes invagination of membrane to form endosome
  2. clatherin coat removed
  3. H+ATPase pumps H ions into endosome to make it acidic
  4. Under pH 5.5 transferrin lets go of iron (pumped out of endosome to make ferritin, heme, etc)
  5. TtR wants to bind to transferrin even tighter in acidic conditions
  6. Endosome goes back to surface via hbd docking protein 7. TfR lets go of transferrin, which bind to new iron
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38
Q

What is the kiss and run hypothesis?

Hint: transfer iron to mitochondria

A

Endosome transiently touches the mitochondria to directly transfer the iron to the mitochondria for heme formation WITHOUT a transport protein

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39
Q

Since transferrin carries iron in Fe3+ form, DMT1 pumps iron out of endosome with help of which enzyme?

A

Steap3 to make Fe2+

ferrireductase

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40
Q

What are some causes of iron deficiency?

A
  • Insufficient dietary iron
  • Menstruation
  • Aspirin abuse
  • Ulcers of GI tract (blood loss)
  • Hypochromic microcytic anemia

Tx with iron supp

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41
Q

Genetic iron overloading is called what? What is the issue?

A

Hereditary Hemochromatosis

Iron absorption increased

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42
Q

Conditional iron overloading is caused by what?

A

repeated blood transfusions such as sickle cell anemia pts or B-thalassemia (no B-globin)

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43
Q

Classical hereditary hemochromatosis is autosomal _________ and has mutation in the HFE gene (hereditary Fe). HFE binds to transferrin receptor

A

recessive
(MC AR dz in men)

(doesn’t show up till 50s)

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44
Q

TQ What does the mutation in the HFE gene lead to? How often do homozygotes have full blown HH?

A

Cys 282 to Tyr (C282Y)

Only 1% of homozygotes have it!

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45
Q
  • HH leads to elevated total body iron w/ ____ _____.
  • This leaves the iron storage organs such as liver, pancreas, and heart at risk!
  • Due to free iron=TOXIC
  • Risk of liver damage, diabetes, heart failure
A

cell injury

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46
Q

How can we test for HH?

A

> 400 ng/ml serum ferritin (protein iron storage, normal is 20-300)

  • CT, MRI, or histo of liver!
  • Total body iron is 15 g (normal 3-5g)
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47
Q

What is the treatment for HH? (2)

A
  • Blood letting (500 ml (1 unit) blood weekly up to 80 weeks then every other month
  • ExJade: iron chelator but serious side effects including death
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48
Q

What is the normal fx of hepcidin?

When iron levels are ok? When iron levels are down?

A
  • Binds ferroportin and causes internalization and proteolysis of ferroportin (no iron into body)
  • Iron replete: hepcidin up and ferroportin down
  • Iron deplete: Hepcidin down and ferroportin up
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49
Q

Hfe binds to TfR1 in low iron conditions. In high iron conditions, then transferrin binds Tfr1 and Hfe is kicked off and binds to TfR2. The binding of Hfe to TrR2 causes what?

A

Signal transduction to increase production of hepcidin (which will decrease ferroportin levels and decrease iron in blood)

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50
Q

In HH conditions, Hfe mutated cannot bind to TfR2. What does this result in?

A

Cannot turn on Hepcidin expression, no control of ferroportin activity, so ferroportin free to bring in more iron–>iron overload

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51
Q

Hfe works through ____ signaling transduction pathway to induce hepcidin expression. BUT there is a second iron sensing path involving BMP and its receptor (affected in which pt group?)

A

smad

Juvenile Hereditary Hemochromatosis

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52
Q

When iron is increased, expression of BMP6 increased. BMP6 binds to BMPR to indue hepcidin expression in the liver. What happens after BMP binds BMPR?

A

RSMAD binds to SMAD4 and together they interact with Hepcidin promotor to induce hepcidin expression.

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53
Q

TQ In juvenile hemochromatosis, a homozygous recessive dz, there can be a mutation in HJV. What is its fx?

A

Hemojuvelin is a co-receptor for BMPR and increases its activity (and therefore incr hepcidin)

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54
Q

If there is no HJV at all, then there is a severe _______ deficiency and increased ferroportin–>SEVERE iron overload

A

hepcidin

Kids get this in teens

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55
Q

TQ In the more rare type of juvenile hemochromatosis, the _____ gene is mutated. What occurs?

A

HAMP (hepcidin antimicrobial peptide)

Hepcidin not binding to ferroportin->iron overload

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56
Q

Iron refractory iron deficiency anemia (IRID) in humans is caused by mutations that affect what gene?

A

TMPRSS6

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57
Q

The mask mouse has a Tmprss6 mutation and is homozygous recessive. With the mutation, it has microcytic, hypochromic anemia due to iron deficiency. Why?

A

TMPRSS6 is a serine-protease that downregulates hepcidin by inactivating HJV, less BMP, less hepcidin–>more ferroportin

If mutated, then elevated hepcidin! Less ferroportin, less iron

Potential therapy for iron overload

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58
Q 
ABO blood group genotypes:
-Group A: IAIA or IAi
-Group B: IBIB or IBi
-Group C: IAIB
-Group O: ii
Gene coding for the ABO blood group has been called the ABH blood group system

DNA for the ABO blood groups
codes for an _______ not a protein. This adds a carbohydrate to the H substance.

A

enzyme

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59
Q

ABO blood groups are adopted blood groups

If you have the “A” gene you make an “A” enzyme that adds what?
Therefore, A and B antigens are not primary gene products but instead are what?

A

a sugar/carb to the H backbone

carbs that are attached to cell proteins with H substance.

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60
Q

Type O blood has _ antigen ONLY

A

H

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61
Q

Type A blood has an A enzyme that adds what?

A

GalNAc (N-acetylgalactosamine)

62
Q

Type B blood has B enzyme that adds what?

A

Gal (Galactose)

63
Q

Type A, B and O antigens are alleles expressed from the same gene (Chr 9 glycosyltransferase). For ABO alleles to be expressed, however, what is required?

A

H-antigen! (Ch 19, fucosyltransferase)

64
Q 
At 6 mo of age, you make an Ab to what you don't express:
Group A makes what antibody?
Group B?
Group AB?
Group O?
A

Group A=anti-B Ab
Group B=anti-A Ab
Group AB=none
Group O=anti-A and anti-B Ab

65
Q

Type O Origin:

  • Exon 6 and 7 code for 77% of the protein
  • Group O is due to a what?
A
  • nucleotide deletion in exon 6, which creates frameshift at nt261 aa 87
  • Get truncated, non-functional enzyme that is unable to add any carb to the H substance…hence type O
66
Q

What makes and A and B group different? (be specific)

A

At aa #268:
A Gly
B Ala
Codes for specificity of enzyme pocket…thats why they add different carbs to H Ag

67
Q

There is only 1 different between type A and O, but _ nucleotide differences between type A and B (4 aa)

A

7

68
Q

Problems in the blood bank involve what?

A

Rrecombination b/t O allele with part of B allele can produce an A allele

69
Q

Type AB blood has __ antigens, ____ antibodies, and can receive and give from/to which blood types?

A

Type AB blood has:

  • AB antigens
  • NO antibodies
  • Receive from A, B, AB, O
  • Give to AB only!
70
Q

Type O blood has __ antigens, ____ antibodies, and can receive and give from/to which blood types?

A

Type O blood has:

  • NO antigens
  • Anti-A and B antibodies
  • Receive from O ONLY
  • Give to A, B, AB, O (universal donor)
71
Q

If the father is type O and the mother is type A, there is a 50% chance of having type A or type O blood if mother is ____________.

A

heterozygous

72
Q

What happens if a person makes no H antigen? What is this phenotype called?

A

The Bombay Phenotype:

-no A or B so blood type O !

73
Q

What if a blood type is unexpected from known parents?

Ex: Father type O, mother type AO, kid is AB?

A

Father must be h/h and child has functional H allele from mother! Father has a B allele but couldn’t use it since no H antigen

74
Q

Bombay phenotype make antibodies to H! Since all other blood groups have H, what must these pts do for blood bank use?

A

Donate their own blood! They are the universal rejectors so accept only from other Bombay types! (Rare)

75
Q

Why do blood banks ask what your race is?

A

blood type more prominent in certain parts of the world
Ex: A=Alaska, Canada
B=Central Asia
O=ALL of South America

76
Q

What are the 2 RH genes and what are they separated by?

A

RHD and RHCE are separated by SMP1

77
Q

The RHD gene is flanked by 2 homologous Rhesus boxes that allow for non-homologous recombination. This leads to what?

A

Loss of RHD and the “d” phenotype

Rh+=RHD and RHCE (DCE)
Rh- = RHCE (dCE)

78
Q

What is hemolytic disease of the newborn (HDN)?

A
  • Rh incompatibility
  • Develop Rh antibodies
  • Occurs when Rh+ man and Rh- woman have a baby.
79
Q

Describe the process of hemolytic disease of the newborn (HDN)? Which pregnancy do we see effects?

A

1st pregnancy: Mother exposed to Rh+ baby and makes anti-Rh

2nd pregnancy: Rh+ fetus attacked by Rh antibodies–>hemolytic disease

80
Q

How do we treat hemolytic disease of the newborn?

A

Give mother Rhogam, which sucks up Rh antigen so that B cell not activated

81
Q

Decreased HFE leads to decreased TFR2–>
Decreased HAMP expression–>
Increased Fe transfer out of enterocytes by ferroportin (no hepcidin)

What dz is this called?

A

Hereditary hemochromatosis

82
Q
  • HFE: Hereditary hemocrhomatosis (classical)
  • HJV: Rare, juvenile, severe
  • HAMP: Hepcidin cant bind ferroportin, juvenile
  • TFR2: Similar pres to HFE, absence of signal transduction to induce hepcidin expression
  • Ferroportin mutation….where is the deletion and what does it result in?
A

Val 162 DEL

Disables ferroprotin-hepcidin interaction

83
Q

What is described?

  • Hemolytic anemia characterized by spherical and fragile RBC that lyse and release hemoglobin
  • Hemolysis, anemia, splenomegaly
  • Mild to severe to fatal
  • Cause by mutations in genes for the erythrocyte membrane skeleton of RBC
A

Hereditary spherocytosis

spherical RBC

84
Q

The erythrocyte membrane skeleton is made up of alpha and beta _______ heterotetramers, and allows for durability and stability of RBCs

A

spectrin
(head to head dimers make tetramers)

note: also composed of actin, tropomyosin, ankyrin, etc

85
Q

How do you test for HS (hereditary spherocytosis)?

A

Osmotic fragility test!
Put normal cells and HS cells into hypotonic solution, water rushes into cell, centrifuge down….normal cells have strong skeleton so solution remains clear where as HS solution cells have burst so bloody!

86
Q

Various sodium concentrations against % hemolysis. HS cells will rupture sooner. Curve shifts….

A

left

87
Q

What is the most common hemolytic anemia in people of northern european descent.

A

Hereditary Spherocytosis (HS)

mostly spectrin/ankyrin defect

88
Q

HS=Hereditary spherocytosis mutation?

AD, northern europe

A

mutation=spectrins, ankyrin, band 3, protein 4.2

89
Q

HE=Hereditary elliptocytosis
mutation?
AD, blacks

A

mutation=spectrins, GPC (glycophorin C), protein 4.1

see reticulocytosis and spherocytosis (elliptical shaped)

90
Q

HPP=Hereditary pyropoikilocytosis
mutation?
AR, blacks

A

mutation= B-spectrin

see microspherocytes, poikilocytes, reticulocytosis (all different sizes)

91
Q

_______ can produce free radicals–>H202, which can damage RBC and cause hemolytic anemia.

A

Oxygen

92
Q

H202 can be removed by what enzyme?

What is the rxn?

A
  • Glutathione peroxidase donates an electron to H202 to form H20.
  • The oxidized glutathione must be altered back to reduced form using NADPH (forming NADP)
93
Q

What generates NADPH, used in eliminating H2O2?

What does a deficiency in this enzyme lead to?

A

G6PD

Decr. G6PD-->
Decr. NADPH-->
Decr. active reduced glutathione-->
Incr. oxygen free radicals (H2O2)-->
hemolytic anemia
94
Q

What is created in G6PD deficiency? What can’t it bind? (hint, formed by interaction of Hb with H202 and free radicals)

A

Methemoglobin

cannot bind O2 because in Fe3+ not Fe2+ state

95
Q

Methemoglobin in G6PD deficiency precipitates to form what? When removed by macrophages, these are called….

A

Methemoglobin precipitates to form Heinz bodies: erythrocyte inclusion (stains purple)

“Bite cells”: Heinz bodies removed by macrophages in spleen

96
Q

G6PD is what kind of disorder? What does this mean for men and women?

A

X-linked:

  • more common in male
  • females have mild, moderate, severe depending on X-chromosome inactivation
97
Q

What distribution does it parallel?

A

Malaria

Due to drug Primaquine (anti-malarial drug)–>peroxide formation

98
Q

Mutations in G6PD lead to deficiency in what?

What does this result in?

A
  • Decreased enzyme synthesis leads to deficiency in NADPH

- Hemolysis-cell membrane weakened by stress due to excess free radicals from H2O2 damage

99
Q

What are the 2 alleles for G6PD deficiency? What are their differences?

A

G6PDA- and G6PDB-

  • G6PDA-: soldiers w/ anti-malarial drug, self-limiting, enzyme has residual activity
  • G6PDB-: Mediterranean, fava bean hemolysis, life threatening, enzyme barely detectable
100
Q 
G6PD def leads to NADPH def-->
Cell membrane weak-->
Hb oxidized to metHb (Heinz bodies)-->
Heinz bodies attached to membrane-->
Bite cells (hemolysis)

_________ + _______ in a neonate in 1-4 days

A

Hyperbilirubinemia + Jaundice

101
Q

Hemoglobin switching:
Embryonic?
Fetal?
Adults?

A

Embryonic (up to 8 wks) : Hb Gower 1 (zeta2, Epsilon2), Hb Gower 2(alpha2, epsilon2), Hb Portland (zeta2,gamma2)

Fetal (8 wks to birth): Hb F (alpha2, gamma2) 8 wks to birth

Adults: Hb A(alpha 2, Beta2)
Hb A2(alpha2, delta2)
102
Q

TQ How many alpha and beta genes do you have?

A

2 alpha and 1 Beta

103
Q

What is the structural abnormality associated with sickle cell dz?

A

-non-functioning Beta globin protein/chain defect

104
Q

What is the quantitative abnormality associated with Thalassemias?

A

-insuff globin chains produced

105
Q

In Sickle cell dz, what leads to the odd sickle shaped RBCs that impeded circulation and cause hemolytic anemia?

A

HbS hemoglobin! (1 aa change)

106
Q

What are some general clinical presentations of sickle cell anemia?

A
  • Pain
  • Organ damage
  • Stroke (prevent w/ transfusions risk of Fe overload)
  • Incr. infections
107
Q

60-70% of sickle cell is in US (blacks! 1:500)

Painful, vaso-occlusive crises–>
infarct. of tissues and organs

Remember: __________ change in Hb

A

qualitative

108
Q

-Dx of sickle cell disease is suspected in which age group? Why not at birth?

A

infants or young children

Healthy at birth due to Hb F but as get older Hb F levels decr & Hb S increases

109
Q
  • Painful swelling of the hands and feet
  • Pallor
  • Jaundice
  • Pneumococcal sepsis or meningitis
  • Severe anemia w/ splenic enlargement
A

Sickle Cell Anemia

110
Q

What is the single mutation that leads to sickle cell anemia?

A

B mutation: GLU6VAL
GAA to GTA Val

HbS
HbC

111
Q

Hb SS–>
Abnormal Hb crystallizes in cell causing sickling–>
____ _________,
Cell clump and block vessels,
Sickle cells accumulate in _____–>
Weakness, anemia, HF, Pain, Fever, Brain damage, ETC

A

RBC breakdown

Sickle cells accumulate in spleen

112
Q

What is the milder form of sickle cell dz that isn’t dx till adulthood?
What is the primary clinical characteristic

A

Hb CC
Glu6LYS (GAA to AAA Lys)
milder!

Sporadic joint pain

113
Q

Allelic heterogeneity:
-Male=HbAS (sickle cell trait) Female=HbAC (normal)

-Male=a, B, Bs Female= a, B, Bc

-Genotype:
aa/aa/BBs and aa/aa/BBc

What is the probability the parents will have an affected HbSC child?

A

25%

      aa/B   aa/Bs aa/B aa/Bc
114
Q

Tx of sickle cell dz

A
  • Stem cell transplant

- Hydroxyurea: chemotherapeutic agent to induce HbF

115
Q

Hb F therapy:

What gene is involved in control of HbF expression? How does it work?

A

KLF1!
When KLF1 low–>
Decreased expression of Bcl11A–>
HbF is expressed

116
Q

KLF1 mutations lead to HPFH, which stands for…

A

Hereditary persistance fetal hemoglobin

People are ok!

117
Q

Alpha thalassemia results in the creation of what? (2)

A

HbH + Hb Bart’s

118
Q

Beta thalassemia results in the creation of what? (3)

A

B+ and Bo

Hb Lepore

119
Q

The thalassemias are found in ppl who originated from where? What is wrong?

A
  • Mediterranean, Africa, Far East

- Decreased globin chain production

120
Q

Which thalassemia is more severe and why? (alpha or beta)

A

Beta is worse! (only 1 B gene)

Alpha is mild because decreased alpha chains but two alpha genes make up for it

121
Q

Thalassemias
Imbalanced ______-_____ synthesis–>
Defective Hb production–>
Damage to RBC

A

globin-chain

122
Q

What are the two mutations possible in B-thalassemia?

A

Single nucleotide change creates a new splice site, which causes frameshift, reach stop codon, shorter protein, degrades

Mutation of normal splice site activates cryptic splice site, frameshift, stop codon, degrades

123
Q

B-thalassemia minor (B+) : one abnormal B-globin gene….usually mild or asymptomatic anemia. What do we see in B-thalassemia major (Bo)? (6)

note: B=normal
Bo= no B-chain expression
B+=partial B-chain expression

A

Two affected B-globin from HBB alleles (serious dz):

  • Decreased Hb production
  • Excess alpha chains=inclusion bodies–>hemolysis of RBC
  • Ineffective erythropoiesis
  • Hyperspleenism (hematopoiesis)
  • Severe anemia with bone changes (Cooley)
  • Blood transfusion leads to Fe overload
124
Q

TQ

Is BBo the same as B+B?

A

NO!!!

  • BBo only has 50% B-globin synthesis
  • Only partial deficiency in B+B
125
Q
  • Ineffective erythropoeisis
  • Hemolytic anemia (from alpha-chain inclusions)
  • Microcytic, Hypochromic anemia
  • Erythroid hyperplasia

you think…

A

B-Thalassemia

126
Q

When do we diagnose thalassemia? Why?

A

Dz seen when HbF–>HbA at 6-12 months of age (neonates)

no switch from gamma to beta

127
Q

Severe anemia w/ low Hb with smear showing:

  • microcytes
  • teardrop cells
  • poikilocytosis
  • target cells
A

B-Thalassemia

128
Q

Tx of B-thalassemia is _____ ________; if done inadequately can lead to face deformities (splaying of teeth, broadened nasal bridge) as well as maxillary marrow hyperplasia + frontal bossing

A

blood transfusion

leads to cause of death due to iron deposition leading to organ failure (HF in 20s to 30s)

129
Q

In alpha-thalassemia, since __ chromosomes (16) have alpha globin, and any/all can be removed (1, 2, 3, or 4)

A

2

130
Q

If reduced alpha-globin chain from HBA genes, excess of B-chains result….this is present in both ____ and _____ Hbs.

A

fetal and adult

131
Q

Deficiency of alpha chains:
Adult: excess beta chains–>tetramers called what?

Fetal: excess gamma chains–>tetramers called what?

A

Adult: excess beta chains–>tetramers (Hb H)

Fetal: excess gamme chains–>tetramers (Hb Bart’s)

132
Q

TQ: alpha-thalassemia is most often caused by what?

A

Deletions
aa/aa =normal
-a/aa =one deleted
–/aa =2 deleted

133
Q

What is described?
-a/aa
silent carrier, one alpha gene deleted

A

a+ thalassemia

alpha+

134
Q

What is being described?

-a/-a or –/aa

A

a0 thalassemia

alpha0

135
Q

What is being described?
3 alpha genes affected
-a/–

A

HbH dz

only 1 alpha gene

136
Q

What is being described?

both alpha genes completely inactivated –/–

A

Hydrops fetalis w/ Hb Bart’s

137
Q

Which thalassemia?
Low MCV (microcytosis)
Low MCH (hypochromia)
Normal % HbA2 and HbF

A

a0 thalassemia

alpha0

138
Q

What is being described?
-Compound heterozygote of a+ and a0
(-a/aa x –/aa = -a/–)
-Excess B chains form B4 tetramers which precipitate slowly as inclusion bodies (Heinz bodies)–>hemolytic anemia

A

Hb H dz

139
Q

Infant/child presents w/…dz?

  • moderately severe anemia
  • microcytic, hypochromic hemolytic anemia
  • hepatosplenomegaly
  • mild jaundice
A

Hb H dz

140
Q 
What is being described?
-Homozygous for a0 thalassemia
(--/aa x --/aa = --/--)
-Make gamma tetramers (Bart's Hb)
-Stillborn/die after birth with generalized edema and severe hypochromic anemia
A

Hydrops fetalis w/ Hb Bart’s

141
Q

Hb Bart’s has a high or low oxygen affinity? What is the result?

A

High! So binds oxygen from mother but doesn’t release to fetal tissue

-Severe hypoxia–>
Edema (hydrops) due to CHF
-massive hepatosplenomegaly

142
Q

TQ: In which pt population are the following more common?
a0 thalassemia with 2 alleles lost:

from the same chromosome?
from different chromosomes?

A

same chromosomes=asians

different chromosomes=africans

143
Q

Why is pt race impt in genetic counseling for thalassemia?

A

Asian family aa/– + aa/– risk of hydrops fetalis VERSUS

african family a-/a- + a-/a- only alpha thalasemia trait

144
Q

HbH Dz: Excess _ chains aggregate to form inclusions. MC found in which pt pop?

A

B

asians

145
Q

Hydrops fetalis: Excess _____ chains (Bart’s Hb) aggregate to form tetramers w/ extreme O2 affinity (heinz bodies)

A

gamma

146
Q

In HbH dz, 3 alpha globin chains are affected.

Newborns express which tetramer? adults?

A

Newborns: Hb Barts (gamma)
Adults: Beta tetramers

147
Q

Delta-beta thalassemias=no HbA or HbA2 made

What are the two types

A

a-delta-B+-Thalassemia make Hb Lepore (normal alpha chain and B fusion chain)

delta-Bo-thalassemia: no delta or B chain made

148
Q

TQ What is delta-Bo-HBHF?
Appearance?
Useful for…

A
  • No HbA but makes lots of HbF
  • Appear normal
  • Basis for therapy to induce HbF in B-thalassemia and sickle cell
149
Q

What is the difference between B-thalassemia and alpha-thalassemia?

A

B-thalassemia:
-Ineffective erythropoiesis
-Excess alpha chains cannot form tetramers so precipitate in red cells
-No HbH or Hb Bart’s
alpha-thalassemia:
-Unstable tetramers HbH + Hb Bart’s precipitate and cause hemolytic anemia
-Not characterized by ineffective erythropoeisis

150
Q

Hemophilia A:

  • X-linked
  • What is mutated?
A

Factor 8

151
Q

Hemophilia B:

  • _________ disease
  • X-linked
  • What is mutated?
A

Christmas disease

Factor 9

152
Q

Since the hemophilia diseases are X-linked, what does this mean for affected male’s with daughters? What about female carriers’ children?

A

All daughters of affected males are carries

Female carries transmit to 50% of children (half the daughters and sons)

SBL Midterm (6 decks)

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