694 first aid ch 02 biochem flashcards

8/12/2019 694 First Aid Ch 02 Biochem Flashcards

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Full-term neonate of uneventfuldelivery becomes mentally

retarded and hyperactive andhas a musty odor.

PKU.

Stressed executive comeshome from work, consumes 7

or 8 martinis in rapid successionbefore dinner, and becomes

hypoglycemic. mech?

NADH increase preventsgluconeogenesis by shuntingpyruvate and oxaloacetate to

lactate and malate.

2-year-old girl has an inabdominal girth, failure to thrive,

and skin and hair depigmentation.Kwashiorkor.

Alcoholic develops a rash,diarrhea, and altered mental

status.low Vitamin B3 (pellagra).

51-year-old man has black spotsin his sclera and has noted thathis urine turns black upon

standing.

Alkaptonuria.

25-year-old male complainsof severe chest pain and has

xanthomas of his Achillestendons.

Familial hypercholesterolemia;
http://www.natures.ir/http://www.natures.ir/


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A woman complains of intensemuscle cramps and darkened

urine after exercise.McArdles disease.

Two parents with albinismhave a son who is normal. . how

Locus heterogeneity.

A 40-year-old man has chronicpancreatitis with pancreatic

insufficiency. What vitamins arelikely deficient?

A, D, E, and K.

Vitamins

name the fat solublesand quick functions

Vitamin AVisionVitamin DBone calcification

Ca2+ homeostasisVitamin KClotting factors

Vitamin EAntioxidant

Vitamins

name the water solubles withaka's

B1 (thiamine: TPP)B2 (riboflavin: FAD, FMN)

B3 (niacin: NAD+)B5 (pantothenate: CoA)

B6 (pyridoxine: PP)B12 (cobalamin)

C (ascorbic acid)BiotinFolate

Vitamins: watersoluble

All wash out easily from body

except

B12 and folate


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B-complex deficiencies oftenresult in

dermatitis,glossitis, and diarrhea.

Vitamin Aaka

retinol

Vitamin A (retinol)

Deficiency

Night blindness, dry skin.

increased suceptability tomeasles

Vitamin A (retinol)

Function

Constituent of visual pigments(retinal).

Vitamin A (retinol)

Excess

Arthralgias, fatigue, headaches,skin changes, sore throat,

alopecia.

retinolaka

Vitamin A

Vitamin A (retinol)

source

Found in leafy vegetables.


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Vitamin A (retinol)

mnemonioc

Retinol is vitamin A, so thinkRetin-A (used topically for

wrinkles and acne).

Vitamin Baka

thiamine

thiamine

aka Vitamin B

Vitamin B1 (thiamine)

Deficiency

Beriberi and Wernicke-Korsakoffsyndrome. Seen in alcoholism

and malnutrition.Spell beriberi as Ber1Ber1.

Vitamin B1 (thiamine)

Function

In thiamine pyrophosphate, acofactor for oxidative

decarboxylation of -keto acids(pyruvate,

-ketoglutarate) and a cofactor fortransketolase in the HMP shunt.

Dry beriberivs

Wet beriberi

Dry beriberipolyneuritis,muscle wasting.

Wet beriberihigh-outputcardiac failure (dilated

cardiomyopathy), edema.

Vitamin B2aka riboflavin


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riboflavinaka

Vitamin B2

Vitamin B2 (riboflavin)

Deficiency

The 2Cs.

Angular stomatitis, Cheilosis,Corneal vascularization.


Function

Cofactor in oxidation andreduction (e.g., FADH2).

"FAD and FMN are derived fromriboFlavin (B2 = 2 ATP)"

Vitamin B3aka

niacin

niacinaka

Vitamin B3

Vitamin B3 (niacin)

Deficiency

Pellagra can be caused by

Hartnup disease ( tryptophanabsorption), malignant carcinoid

syndrome (tryptophanmetabolism), and INH

( vitamin B6).

Pellagras symptoms are the 3

Ds: Diarrhea, Dermatitis,Dementia (also beefyglossitis).


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Vitamin B3 (niacin)

Function

Constituent of NAD+, NADP+(used in redoxreactions). Derivedfrom tryptophan using vitamin B6.

NAD derived from Niacin(B3 = 3 ATP).

Diarrhea, Dermatitis,Dementia (also beefy

glossitis).Pellagra

Pellagras symptomsthe 3 Ds: Diarrhea, Dermatitis,

Dementia (also beefyglossitis).

pantothenateaka

Vitamin B5

Vitamin B5aka

pantothenate

Vitamin B5 (pantothenate)Deficiency

Dermatitis, enteritis, alopecia,adrenal insufficiency.

Vitamin B5 (pantothenate)

Function

Constituent of CoA (a cofactor foracyl transfers)

and component of fatty acidsynthase.

Pantothen-A is in Co-A.


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pyridoxineaka

Vitamin B6

Vitamin B6aka

pyridoxine

Vitamin B6 (pyridoxine)

Deficiency

Convulsions, hyperirritability(deficiency inducible by INH and

oral contraceptives),peripheral neuropathy.


Function

Converted to pyridoxalphosphate, a cofactor used intransamination (e.g., ALT and

AST),

decarboxylation, and hemesynthesis.

Vitamin B12aka

cobalamin

cobalaminaka

Vitamin B12

Vitamin B12 (cobalamin)

Deficiency

Macrocytic, megaloblasticanemia; neurologic

symptoms (optic neuropathy,subacute combineddegeneration, paresthesia);

glossitis.


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Function

Cofactor for homocysteinemethylation

(transfers CH3 groups asmethylcobalamin)

and methylmalonyl-CoA handling.


source and storage

Found only in animal products.

Stored primarily in the liver.Very large reserve pool (several

years).


causes of deficiency

Vitamin B12 deficiency isusually caused by

malabsorption (sprue,enteritis, Diphyllobothriumlatum), lack of intrinsic factor

(pernicious anemia), or absenceof terminal ileum

(Crohns disease).


testing

Use Schilling test to detectdeficiency.


syntesized by

Synthesized only bymicroorganisms.

schilling test rocess

the patient is given radiolabeledvitamin B12 to drink A normalresult shows at least 5% of theradiolabelled vitamin B12 in the

urine over the first 24 hours.


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Folic acid

Deficiency

Macrocytic, megaloblastic anemia(often no neurologic symptoms,

as opposed to vitamin B12deficiency).

Folic acid

Function

Coenzyme (tetrahydrofolate) for1-carbon

transfer; involved in methylationreactions.

Important for the synthesis ofnitrogenous basesin DNA and RNA.

Folic acid

sourceFOLate from FOLiage.

what is PABA and implications

PABA is the folic acidprecursor in bacteria. Sulfa

drugs and dapsone(antimicrobials) are PABA

analogs.

the folic acidprecursor in bacteria

PABA

Most common vitamin deficiencyin the United

States.Folic acid


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Biotin

Deficiency

Dermatitis, enteritis. Caused byantibiotic use,

ingestion of raw eggs.

AVIDin in egg whitesAVIDly binds biotin.

Biotin

Function

Cofactor for carboxylations:1. Pyruvate oxaloacetate

2. Acetyl-CoA malonyl-CoA3. Proprionyl-CoA methylmalonyl-CoA

Vitamin C (ascorbic acid)

Deficiency

Scurvyswollen gums, bruising,anemia, poor wound healing.


Function

Necessary for hydroxylation ofproline and lysine incollagen synthesis.

Facilitates iron absorption bykeeping iron in Fe+2

reduced state (more absorbable)Necessary as a cofactor for

dopamine NE.


role in collagen formation

Vitamin C Cross-linksCollagen. Necessary for

hydroxylation of proline and lysinein collagen synthesis.

Vitamin D

different forms and locations

D2 = ergocalciferol, consumed inmilk.

D3 = cholecalciferol, formed insun-exposed skin.

25-OH D3 = storage form.

1,25 (OH)2 D3 = active form.


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Vitamin D

Deficiency

Rickets in children (bendingbones), osteomalacia

in adults (soft bones), andhypocalcemic tetany.

Vitamin D

Function

intestinal absorption of calciumand phosphate.

Vitamin D

Excess

Hypercalcemia, loss of appetite,stupor. Seen in

sarcoidosis, a disease where theepithelioidmacrophages convert vitamin D

into its active form.

Vitamin E

Deficiency

Increased fragility of erythrocytes,neurodysfunction.

Vitamin E is for Erythrocytes.

Vitamin E

Function

Antioxidant (protects erythrocytesfrom hemolysis).

Vitamin E is for Erythrocytes.

Vitamin K

Deficiency

Neonatal hemorrhage with PTand aPTT but normal bleeding

time,

Vitamin K

Function

Catalyzes -carboxylation ofglutamic acid residues

on various proteins concernedwith blood clotting.


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A, D, E, K. Absorption dependenton

gut (ileum) and pancreas.

Angular stomatitis, Cheilosis,Corneal

vascularization.


Deficiency

Dermatitis, enteritis, alopecia,

adrenal insufficiency.

Vitamin B5 (pantothenate)

Deficiency

Convulsions, hyperirritability(deficiency inducible by INH and

oral contraceptives),peripheral neuropathy.


Deficiency

Macrocytic, megaloblasticanemia; neurologic

symptoms (optic neuropathy,subacute combined

degeneration, paresthesia);glossitis.


Deficiency

Macrocytic, megaloblastic anemia(often no

neurologic symptoms, as opposedto vitamin

B12 deficiency).

Folic acid

Deficiency

Dermatitis, enteritis. Caused byantibiotic use,

Biotin

Deficiency


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Increased fragility of erythrocytes,neurodysfunction.

Vitamin EDeficiency

Ethanol metabolism

limiting reagentNAD+ is the limiting reagent.

Disulfiram (Antabuse)

mech

inhibits acetaldehydedehydrogenase (acetaldehyde

accumulates, contributing tohangover symptoms).

Disulfiramaka

Antabuse

Antabuse Disulfiram

Ethanol hypoglycemia

mech

Ethanol metabolism

NADH/NAD+ ratio in liver, causingdiversion of pyruvate to lactate

and OAA to malate, therebyinhibiting gluconeogenesis

fatty change mech NADH/NAD+ ratio in liver with

shunting away from glycolysis and

toward fatty acid synthesis


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Kwashiorkor

causes

Kwashiorkor results from aprotein-deficient MEAL:

MalabsorptionEdema

AnemiaLiver (fatty)

Kwashiorkor

protein malnutrition resulting inskin

lesions, edema, liver malfunction(fatty change).

Clinical picture is small child withswollen belly.

protein malnutrition resulting in

skin lesions, edema, livermalfunction (fatty change).

Clinical picture is small child withswollen belly.

Kwashiorkor

Marasmus

energy malnutrition resulting intissue and muscle wasting, loss of

subcutaneousfat, and variable edema.

energy malnutrition resulting intissue and muscle wasting, loss of

subcutaneousfat, and variable edema.

Marasmus

Chromatinstructure

() charged DNA loops twicearound nucleosome

core (2 each of the (+) chargedH2A, H2B, H3,

and H4) to form nucleosomebead.H1 ties nucleosomestogether in a string (30-nm

fiber).


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the only histone that is notin the nucleosome core.

H1 is

H1 isthe only histone that is notin the nucleosome core.

Heterochromatin

Condensed, transcriptionally

inactive Chromatin

Condensed, transcriptionallyinactive Chromatin

Heterochromatin

Less condensed, transcriptionallyactive Chromatin

Euchromatin

EuchromatinLess condensed, transcriptionally

active Chromatin

Nucleotides

ring number

Purines (A, G) have 2 rings.Pyrimidines (C, T, U)

have 1 ring.


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Deamination of ???? makesuracil.

cytosine

Deamination of cytosine makes????.

uracil.

Amino acids necessary for purine

synthesis:

Glycine

AspartateGlutamine

which Nucleotide

has a methylThymine

which Nucleotide

has a ketoneGuanine

Nucleotideswhich are which

-Purines (A, G) PURe As Gold:

PURines.

-Pyrimidines (C, T, U) CUT thePY (pie): PYrimidines.

Nucleotides (base + ribose +

phosphate) are linked by

3-5 phosphodiester bond.


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Nucleotides are made of whatthree things

base + ribose + phosphate

NucleotidesTransition vs. transversion

Transition-Substituting purine forpurine or pyrimidine for

pyrimidine. ( TransItion = Identicaltype.)

Transversion Substituting purinefor pyrimidine or visa versa.(TransVersion = conVersion

between types).

Genetic code features andexceptions

Unambiguous

Each codon specifies only oneamino acid.

no exceptions


Degenerate/redundant

More than one codon may codefor the sameamino acid.

Methionine encoded by onlyone codon.

Genetic code features and

exceptions

Commaless, nonoverlapping

Read from a fixed starting pointas a continuous

sequence of bases.

Some viruses are an exception.


Universal

Genetic code is conservedthroughout evolution.

Exceptions include

mitochondria, archaebacteria,Mycoplasma, and some yeasts.


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Mutations in DNA

Silent

Same aa, often base change in3rd position of

codon (tRNA wobble).

Mutations in DNA

Same aa, often base change in3rd position of

codon (tRNA wobble).

Silent

Mutations in DNA

Missense

Changed aa (conservativenew

aa is similarin chemical structure).

Mutations in DNA

Changed aa (conservativenewaa is similar in chemical

structure).

Missense

Mutations in DNA

Nonsense

Change resulting in early stopcodon.

Mutations in DNA

Change resulting in early stopcodon.

Nonsense

Mutations in DNA

Frame shift

Change resulting in misreading ofall nucleotides

downstream, usually resulting in a

truncatedprotein.


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Mutations in DNA

Change resulting in misreading ofall nucleotides

downstream, usually resulting in atruncated

protein.

Frame shift

point Mutations in DNA

Severity of damage

Severity of damage: nonsense> missense > silent.

DNA replication and DNApolymerases

who has multiple origins ofreplication.

Eukaryotic genome


Eukaryotes Replication begins at

Replication begins at a consensussequence of

AT-rich base pairs.


who has Single origin of

replication

Prokaryotes


Create a nick in the helix torelieve supercoils.

DNAtopoisomerases


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function/activity of DNAtopoisomerases

Create a nick in the helix torelieve supercoils.


Makes an RNA primer on whichDNA

polymerase III can initiatereplication.

Primase


function/activity of Primase

Makes an RNA primer on whichDNA

polymerase III can initiatereplication.


Elongates the chain by addingdeoxynucleotides to the 3 end

until it reachesprimer of preceding fragment. 3

5exonuclease activity proofreads

each addednucleotide.

DNA polymeraseIII


function/activity of DNA

polymeraseIII

Elongates the chain by addingdeoxynucleotides to the 3 end

until it reachesprimer of preceding fragment. 3

5

exonuclease activity proofreadseach addednucleotide.


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Degrades RNA primer and fills inthe gap

with DNA.

DNA polymerase I


function/activity of DNApolymerase I

Degrades RNA primer and fills inthe gap

with DNA.


Seals.

DNA ligase


function/activity of DNA ligase

Seals.

??????? has5 3 synthesis and

proofreads with 3 5exonuclease.

DNA polymerase III

??????? excisesRNA primer with 5 3

exonuclease.DNA polymerase I


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DNA repair

Nucleotide excisionrepair

Specific endonucleases releasethe oligonucleotide-

containing damaged bases; DNApolymerase and

ligase fill and reseal the gap,respectively.

DNA repair

Specific endonucleases releasethe oligonucleotide-

containing damaged bases; DNApolymerase and

ligase fill andreseal the gap,

respectively.


DNA repair

Base excision repair

Specific glycosylases recognizeand remove damaged

bases, AP endonuclease cutsDNA at apyrimidinic

site, empty sugar is removed, andthe gap is filled

and resealed.DNA repair



site, empty sugar is removed, andthe gap is filledand resealed.


DNA repair

mutation in Nucleotide excisionrepair

Mutated in xerodermapigmentosa (dry skin with

melanoma and other cancers).


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DNA repair

mutation in xerodermapigmentosa


DNA repair





DNA repair





Mismatch repair

Unmethylated, newly synthesized

string is recognized, Mmismatched nucleotides are

remove, and the gap isfilled and resealed.

DNA repair

Unmethylated, newly synthesized

string is recognized, Mmismatched nucleotides are

remove, and the gap isfilled and resealed.

Mismatch repair

DNA repair

Mutation in hereditarynonpolyposis colon cancer.

Mismatch repair


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DNA repair

Nonhomologousend joining

Brings together two ends of DNAfragments. No requirement for

homology.

DNA repair

Brings together two ends of DNAfragments. No requirement for

homology.

Nonhomologousend joining

DNA/RNAsynthesis direction

DNA and RNA are bothsynthesized 5 3.

Remember that the 5 of theincoming nucleotidebears the triphosphate (energy

source for bond).The 3 hydroxyl of the nascent

chain is the target.

protein synthsynthesis direction

Protein synthesis also proceeds

in the 5 to 3 direction.Amino acids are linked

N to C.

Types of RNAand descriptions

Massive, Rampant, Tiny.

mRNA is the largest type of RNA.rRNA is the most abundant type

of RNA.tRNA is the smallest type of RNA.

RNA polymerases

EukaryotesI,II,III

RNA polymerase I makes rRNA.RNA polymerase II makes mRNA.RNA polymerase III makes tRNA.


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RNA polymerases

Prokaryotes

RNA polymerase (multisubunitcomplex) makes

all 3 kinds of RNA.

-amanitinfound in death cap mushrooms.

inhibits RNA polymerase II.

found in death cap mushrooms.

inhibits RNA polymerase II. -amanitin

RNA polymerases

proofreading

No proofreading function, but caninitiate chains.

???? opens DNA at promoter siteRNA polymerase II opens DNA at

promoter site

mRNA initiationcodons

AUG (or rarely GUG).

AUG inAUGurates proteinsynthesis.

mRNA stop codonsUGA = U Go Away.UAA = U Are Away.

UAG = U Are Gone.


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Promoter

Site where RNA polymerase andmultiple other

transcription factors bind to DNAupstream from

gene locus (AT-rich upstreamsequence with

TATA and CAAT boxes).Site where RNA polymerase and

multiple othertranscription factors bind to DNA

upstream fromgene locus (AT-rich upstream

sequence with

TATA and CAAT boxes).

Promoter

Stretch of DNA that alters geneexpression by binding

transcription factors. May belocated close to, far

from, or even within (in an intron)the gene whose

expression it regulates.

Enhancer

Enhancer

Stretch of DNA that alters geneexpression by binding

transcription factors. May belocated close to, far

from, or even within (in an intron)the gene whose

expression it regulates.

Promoter mutation commonlyresults in

dramatic inamount of gene transcribed.

Site where negative regulators(repressors) bind.

Operator


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OperatorSite where negative regulators

(repressors) bind.

Introns vs.exons

Exons contain the actual geneticinformation coding for protein.

Introns are intervening noncodingsegments of DNA.

Splicing of mRNA

steps

Primary transcript combines

with snRNPs to form

spliceosome.Lariat-shaped intermediate is

generated.

Lariat is released to remove

intron precisely and join twoexons.

RNA processing(eukaryotes)

where

Occurs in nucleus. Aftertranscription:


steps

1. Capping on 5 end (7-methyl-G)2. Polyadenylation on 3 end (

200 As)3. Splicing out of introns


names

Initial transcript is calledheterogeneous nuclear

RNA (hnRNA).Capped and tailed transcript is

called mRNA.


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Only ???????? RNA istransported out of the

nucleus.processed


wrt transport

Only processed RNA istransported out of the

nucleus.

tRNA

Structure

7590 nucleotides, cloverleafform, anticodon end is opposite 3

aminoacyl end. AlltRNAshave CCA at 3 end whereaa's are bound

tRNA ChargingAminoacyl-tRNA synthetase (1

per aa, uses ATP)

where is error protection in proteinsynthesis

in TRNA charging. once aa is onthere it will put on a wrong aa

Protein synthesis

Initiation

Initiation factors (IFs) help

assemble the 30Sribosomal subunit with the initiator

tRNA, arereleased when the mRNA and the

ribosomalsubunit assemble with the

complex.


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Protein synthesis

elongation steps

1. Aminoacyl tRNA binds to Asite.

2. Peptidyltransferase catalyzespeptide bond

formation, transfers growingpolypeptide to ami

acid in A site.3. Ribosome advances three

nucleotides toward 3end of RNA, moving peptidyl RNA

to P site.

Protein synthesis

A siteA site = incoming AminoacyltRNA.

Protein synthesis

P site

P site = accommodates growingPeptide.

Protein synthesis

E site

E site = holds Empty tRNA asit Exits.

Protein synthesis

ATP vs GTP

ATPtRNA Activation(charging).

GTPtRNA Gripping andGoing places (translocation).

Posttranslational modifications

Trimming

Removal of N- or C-terminal pro-

peptides from zymogens togenerate mature proteins.


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Covalent alterations

Phosphorylation, glycosylation,and hydroxylation.


Proteasomal degradation

Attachment of ubiquitin todefective proteins to tag them for

breakdown.

Cell cycle phases

shortest phase Mitosis

Cell cycle phases

Permanent cells what andexamples

Remain in G0, regenerate fromstem cells.

Never go to G0, divide rapidly

with a short G1.

Cell cycle phases

Stable cells what and examples

Enter G1 from G0 whenstimulated.

Hepatocytes, lymphocytes.

Cell cycle phases

Labile cells what and examples

Never go to G0, divide rapidly

with a short G1.

Bone marrow, gut epithelium,skin, hair follicles.

Checkpoints controltransitions between

phases. Regulated by

cyclins, cdks, and

tumor suppressors.


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RER is the site of

synthesis of secretory (exported)proteins and of N-linkedoligosaccharide addition

to many proteins.

the site of synthesis of secretory(exported)proteins and of N-linkedoligosaccharide addition

to many proteins.

RER

Mucus-secreting goblet cells ofthe small intestine and

antibody-secreting plasmacells are rich in

RER.

what cells are particularly rich inRER.

Mucus-secreting goblet cells ofthe small intestine and

antibody-secreting plasmacells

SER is the site ofsteroid synthesis and

detoxificationof drugs and poisons.

the site of steroid synthesis anddetoxification

of drugs and poisons.SER

what cells are particularly rich in

SER.

Liver hepatocytes andsteroid hormoneproducing

cells of the adrenal cortex


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Liver hepatocytes andsteroid hormoneproducingcells of the adrenal cortex

are rich in

SER.

6 Functions of Golgiapparatus

1. Distribution center of proteinsand lipids from

ER to the plasma membrane,lysosomes, and

secretory vesicles2. Modifies N-oligosaccharides

3. Adds O-oligosaccharides4. Addition of mannose-6-

phosphate5. Proteoglycan assembly

6. Sulfation

I-cell disease

mech

failure of addition of mannose-6-phosphate to

lysosome proteins, enzymesare secreted outside the cell

instead of being targeted tothe lysosome.

failure of addition of mannose-6-phosphate to

lysosome proteins, enzymesare secreted outside the cellinstead of being targeted to

the lysosome.

I-cell disease:

I-cell disease

clinical findings

Characterized by coarse facialfeatures, clouded corneas,restricted joint movement,and high plasma levels oflysosomal enzymes. Often

fatal in childhood.


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Characterized by coarse facialfeatures, clouded corneas,restricted joint movement,and high plasma levels oflysosomal enzymes. Often

fatal in childhood.

I-cell disease

clinical findings

Vesicular trafficking proteins:

COP I

Retrograde,Golgi ER.


Retrograde,Golgi ER.

COP I


COP II

Anterograde,RER cis-Golgi.


Anterograde, RER cis-Golgi.COP II


Clathrin

trans-Golgi lysosomes, plasma

membrane endosomes(receptor-mediated

endocytosis).


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trans-Golgi lysosomes, plasma

membrane endosomes(receptor-mediated

endocytosis).

Clathrin

Microtubule

structure

Cylindrical structure 24 nm indiameter and of variablelength. A helical array ofpolymerized dimers of -

and -tubulin (13 percircumference). Each dimer

has 2 GTP bound.

Microtubule

functions

has 2 GTP bound. Incorporatedinto flagella, cilia,

mitotic spindles.Microtubules arealso involved in slow axoplasmic

transport in neurons.

Microtubule

speedsGrows slowly, collapses quickly.

Drugs that act on microtubules:

1. Mebendazole/thiabendazole(antihelminthic)

2. Taxol (antibreast cancer)

3. Griseofulvin (antifungal)4. Vincristine/vinblastine

(anti-cancer)5. Colchicine (anti-gout)

is due to a microtubulepolymerization defect

resulting in phagocytosis.

Chdiak-Higashi syndrome


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Plasma membrane compositionwith %'s

Asymmetric fluid bilayer.Contains cholesterol (~50%),

phospholipids (~50%),sphingolipids, glycolipids,

and proteins.

Plasma membrane wrt cholesterolHigh cholesterol or long saturated

fatty acid content increasedmelting temperature.

Phosphatidylcholine

aka lecithin

lecithinaka

Phosphatidylcholine

Phosphatidylcholine(lecithin) function

Major component of RBCmembranes, of myelin, bile, and

surfactant (DPPCdipalmitoyl PC).

Used in esterification ofcholesterol (LCAT is lecithin-

cholesterol acyltransferase).

Major component of RBCmembranes, of myelin, bile, and

surfactant

Phosphatidylcholine(lecithin)


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Organizes and strengthensextracellular matrix.

Collagen

Collagen Types

Type I

(90%)Bone, Skin, Tendon,dentin, fascia, cornea, late wound

repair.

Collagen Types

Bone, Skin, Tendon, dentin,fascia, cornea, late wound repair.

Type I

Collagen Types

Type II

Cartilage (including hyaline),vitreous body, nucleus pulposus.

Type II: carTWOlage.

Collagen Types

Cartilage (including hyaline),vitreous body, nucleus pulposus.

Type II

Type II: carTWOlage.

Collagen Types

Type III (Reticulin)

skin, blood vessels, uterus,fetal tissue, granulation tissue.

Collagen Types

skin, blood vessels, uterus,fetal tissue, granulation tissue.

Type III (Reticulin)


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Collagen Types

Type IV

Basement membrane or basallamina.

Type IV: Under the floor(basement membrane)..

Collagen Types

Basement membrane or basallamina.

Type IV

Type IV: Under the floor(basement membrane).

Collagen

Type III aka Reticulin

Reticulin aka Type III Collagen

Collagen synthesis and structure

steps inside fibroblasts and whereinside of them

1. Synthesis (RER)2. Hydroxylation

(ER)3. Glycosylation

(Golgi)4. Exocytosis


steps outside fibroblasts

5. Proteolyticprocessing

6. Cross-linking


Synthesis (RER)

Translation of collagen chains(preprocollagen)

usually Gly-X-Y polypeptide (Xand Y areproline, hydroxyproline, or

hydroxylysine).


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Translation of collagen chains(preprocollagen)

usually Gly-X-Y polypeptide (Xand Y are

proline, hydroxyproline, orhydroxylysine).

1. Synthesis (RER)


Hydroxylation of specific prolineand lysine

residues (requires vitamin C).

2. Hydroxylation(ER)


Hydroxylation(ER)

Hydroxylation of specific prolineand lysine

residues (requires vitamin C).


Glycosylation of pro--chainlysine residues and

formation of procollagen (triplehelix of three

collagen chains).

Glycosylation(Golgi)


Glycosylation(Golgi)

Glycosylation of pro--chainlysine residues and

formation of procollagen (triplehelix of three

collagen chains).


Exocytosis of procollagen intoextracellular

space.

4. Exocytosis


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4. Exocytosis

Exocytosis of procollagen intoextracellular

space.



Cleavage of terminal regions ofprocollagen

transforms it into insolubletropocollagen.


Cleavage of terminal regions ofprocollagentransforms it into insoluble

tropocollagen.



6. Cross-linking

Reinforcement of many staggeredtropocollagen

molecules by covalent lysine-hydroxylysine cross-linkage (by

lysyl oxidase) to make col-lagen fibrils.


Reinforcement of many staggeredtropocollagen

molecules by covalent lysine-

hydroxylysine cross-linkage (bylysyl oxidase) to make col-

lagen fibrils.

6. Cross-linking


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44/112

Elastin

what and where

Stretchy protein within lungs,large arteries, elastic

ligaments.

Elastin

structure

Rich in proline and lysine,nonhydroxylated forms.

Elastin

wrt diseases

Emphysema can be caused by

excess elastase activity.

????? inhibits elastase. 1-antitrypsin

1-antitrypsin inhibits ?????? elastase.

Marfans syndrome is causedby a defect in?

fibrillin.

Metabolism sites

Mitochondria only

Fatty acid oxidation (-oxidation),acetyl-CoA production, Krebs

cycle.


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Metabolism sites

Cytoplasm only

Glycolysis, fatty acid synthesis,HMP shunt, protein synthesis

(RER), steroid synthesis(SER).

Metabolism sites

Both Mitochondria and Cytoplasm

heme synthesis, urea cycle,Gluconeogenesis,

"HUGs take 2"

Aerobic metabolism of glucose

produces ???? via malate shuttle, 38 ATP

Aerobic metabolism of glucoseproduces ???? via G3P shuttle.

36

Aerobic metabolism of glucoseproduces 38 ATP via

malate shuttle

Aerobic metabolism of glucoseproduces 36 ATP via

G3P shuttle.

Anaerobic glycolysis produces

???? per glucose molecule.

only 2 net ATP


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Activated carriers (whatcarries/what is carried by)

ATP

Phosphoryl


Phosphoryl

(ATP).


Electrons(NADH, NADPH, FADH2).


NADH, NADPH, FADH2

Electrons


Acyl

(coenzyme A, lipoamide).


coenzyme A

Acyl


lipoamide

Acyl


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48/112


Aldehydes

(TPP).

Rate-determining enzymes ofmetabolic processes

(process/enzyme)

De novo pyrimidinesynthesis

Aspartate transcarbamylase(ATCase)


(process/enzyme)

Aspartate transcarbamylase(ATCase)

De novo pyrimidinesynthesis


(process/enzyme)

De novo purinesvnthesis

Glutamine-PRPP

amidotransferase


(process/enzyme)

Glutamine-PRPPamidotransferase

De novo purinesvnthesis


(process/enzyme)

Glycolysis

PFK-1


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(process/enzyme)

PFK-1

Glycolysis

Rate-determining enzymes ofmetabolic processes(process/enzyme)

F 1,6-bisphosphotase (FBP-1)

Gluconeogenesis


(process/enzyme)

Gluconeogenesis

F 1,6-bisphosphotase (FBP-1)


(process/enzyme)

TCA cycle

lsocitrate dehydrogenase


(process/enzyme)

lsocitrate dehydrogenase

TCA cycle

Rate-determining enzymes of

metabolic processes(process/enzyme)

Glycogen synthesis

Glycogen synthase


(process/enzyme)

Glycogen synthase

Glycogen synthesis


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(process/enzyme)

Glycogenolysis

Glycogen phosphorylase



Glycogenolysis


(process/enzyme)

HMP shunt

Glucose-6-phosphate

dehydrogenase (G6PD)


(process/enzyme)

Glucose-6-phosphatedehydrogenase (G6PD)

HMP shunt


(process/enzyme)

Fatty acid synthesis

Acetyl-CoA carboxylase (ACC)


(process/enzyme)

Acetyl-CoA carboxylase (ACC)

Fatty acid synthesis


(process/enzyme)

Fatty acid oxidation

Carnitine a~~ltransferase I


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(process/enzyme)

Carnitine a~~ltransferase I

Fatty acid oxidation


Ketogenesis

HMG-CoA synthase


(process/enzyme)

HMG-CoA synthase

Ketogenesis


(process/enzyme)

HMG-CoA reductase

Cholesterol synthesis


(process/enzyme)


HMG-CoA reductase

Rate-determining enzymes of

metabolic processes(process/enzyme)

Heme synthesis

ALA synthase


(process/enzyme)

ALA synthase

Heme synthesis


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(process/enzyme)

Carbamoyl phosphate synthase I

Urea cycle


Urea cycle

Carbamoyl phosphate synthase I

ATP + methionine

S-adenosyl-

methionine (SAM)

SAM

function/regeneration

SAM the methyl donor man.

SAM transfers methyl units.Regeneration of methionine (and

thus SAM) isdependent on vitamin B12.

Universal electronacceptors

Nicotinamides (NAD+, NADP+)and flavin

nucleotides (FAD+).

NADPH is a product of the HMP shunt.

NAD+ is generally used in

catabolic processes to

carry reducing equivalents awayas NADH.


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NADPH is generally used in

anabolic processes (steroidand fatty acid synthesis) as a

supply of reducingequivalents.

NADPH is used in:1. Anabolic processes2. Respiratory burst

3. P-450

?????is used in:

1. Anabolic processes2. Respiratory burst3. P-450

NADPH

Hexokinase

WRTlocations, affinity, capacity,

inhibition

(ubiquitous)High affinity,low capacity.

Feedback inhibited by glucose-6-

phosphate.Glucokinase

WRTlocations, affinity, capacity,

inhibition

(liver)Low affinity,

high capacity.No feedback inhibition.

Glucokinase

role

Phosphorylates excess glucose(e.g., after a meal) to sequester

it in the liver.

Phosphorylates excess glucose(e.g., after a meal) to sequester

it in the liver.

Glucokinase


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55/112

Arsenic

mech and clinical findings

Arsenic inhibits lipoic acid(Pyruvate dehydrogenase

complex cofactor):

Vomiting, Rice water stoolsGarlic breath

Vomiting, Rice water stoolsGarlic breath

Arsenic

Pyruvate dehydrogenase complex

reaction

Reaction: pyruvate + NAD+ +CoA acetyl-CoA + CO2 +

NADH.

Pyruvate dehydrogenase complex

activated by

Activated by exercise: NAD+/NADH ratio

ADP

Ca2+

the only purely ketogenic aminoacids.

Lysine and Leucine

Pyruvate dehydrogenasedeficiency

mech

Causes backup of substrate(pyruvate and alanine),resulting in lactic acidosis. Can be

congenital oracquired (as in alcoholics due to

B1 deficiency).

Pyruvate dehydrogenase

deficiency

findings

neurologic defects.


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Pyruvate dehydrogenasedeficiency

Tx

intake of ketogenic nutrients(e.g., high fat content or lysine

and leucine).

# are needed to generate glucosefrom pyruvate.

6 ATP equivalents

Pyruvate metabolism

Alanine

carries amino groups

to the liver from muscle.

Pyruvate metabolism

Oxaloacetate

can replenishTCA cycle or be used in

gluconeogenesis.

Cori cycle

mech and why

Transfers excess reducingequivalents from RBCs and

muscle to liver, allowingmuscle to function

anaerobically (net 2 ATP).Shifts metabolic burden to the

liver.Transfers excess reducingequivalents from RBCs and

muscle to liver, allowingmuscle to function

anaerobically (net 2 ATP).Shifts metabolic burden to the

liver.

Cori cycle


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58/112

Oxidative phosphorylationpoisons

UCP, 2,4-DNP, aspirin

Uncoupling agents

permeability of membrane,causing a proton

gradient and O2 consumption.ATP synthesis stops, but electron

transport continues.Oxidative phosphorylation

poisons

Rotenone, CN, antimycin A,CO

Electron transportinhibitors

Oxidative phosphorylation

poisons

Directly inhibit electron transport,causing a

proton gradient and block of ATPsynthesis.

Electron transportinhibitors

-Rotenone,-cyanide,

-antimycin A,-CO

Oxidative phosphorylation

poisons

Directly inhibit mitochondrialATPase, causing

an proton gradient, but no ATPis produced

because electron transport stops.

ATPase inhibitors

Oligomycin

Oxidative phosphorylationpoisons

Oligomycin

ATPase inhibitors

Directly inhibit mitochondrialATPase, causing

an proton gradient, but no ATPis produced

because electron transport stops.


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Gluconeogenesis, irreversibleenzymes (where, what,

regulation/requirements)

Pyruvate carboxylase

In mitochondria.Pyruvate oxaloacetate.

Requires biotin, ATP.Activated by acetyl-CoA.

Gluconeogenesis, irreversibleenzymes

In mitochondria.Pyruvate oxaloacetate.

Requires biotin, ATP.Activated by acetyl-CoA.

Pyruvate carboxylase


requirements)

PEP carboxykinase

In cytosol.Oxaloacetate

phosphoenolpyruvate.

Requires GTP.


In cytosol.Oxaloacetate

phosphoenolpyruvate.

Requires GTP.

PEP carboxykinase

Gluconeogenesis, irreversible

enzymes (where, what,regulation/requirements)

Fructose-1,6-bisphosphatase

In cytosol.

Fructose-1,6-bisphosphate fructose-6-P.


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In cytosol.

Fructose-1,6-bisphosphate

fructose-6-P.

Fructose-1,6-bisphosphatase


regulation/requirements)

Glucose-6-phosphatase

In ER. Glucose-6-P glucose.


name them

Pathway Produces FreshGlucose.

-Pyruvate carboxylase-PEP carboxykinase

-Fructose-1,6-bisphosphatase-Glucose-6- phosphatase


In ER. Glucose-6-P glucose.

Glucose-6-phosphatase

Gluconeogenesis, irreversible

enzymes

locations in body

Above enzymes found only in

liver, kidney, intestinal epithelium.Muscle cannotparticipate in gluconeogenesis.

Deficiency of the keygluconeogenic enzymes causes

hypoglycemia.


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Pentose phosphate pathway(HMPshunt)

why

Produces NADPH, which isrequired for fatty acid and steroid

biosynthesis and forglutathione reduction inside

RBCs. and nucleotide synthesis


where (in the the cell and body

All reactions of this pathway occurin the cytoplasm.

Sites: lactating mammary glands,liver, adrenal cortexall sites of

fatty acid or steroidsynthesis.


wrt ATP

No ATP is used or produced.

Pentose phosphate pathwayaka

HMP shunt

HMP shunt aka Pentose phosphate pathway


Oxidative reaction features, keyenzymes, and products (with

reasons)

(irreversible)

Glucose-6-phosphatedehydrogenase

NADPH


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Nonoxidative reaction features,

key enzymes, and products (withreasons)

(reversible)

Transketolases (require thiamine)

Ribose-5-phosphate (Ribose-5-phosphate (for

nucleotide synthesis), G3P,F6P (glycolytic intermediates)


deficiency

who

G6PD deficiency is moreprevalent among blacks.


deficiency

histo

Heinz bodiesalteredHemoglobin precipitates

within RBCs.


deficiency

clinical findings

hemolytic anemia due to poorRBC defense against oxidizing

agents (fava beans,sulfonamides, primaquine) and

antituberculosis drugs.

hemolytic anemia due to poorRBC defense against oxidizing

agents (fava beans,

sulfonamides, primaquine) andantituberculosis drugs.


deficiency

Fructose intolerance

mech

deficiency of aldolase B(recessive). fructose-1-phosphate

accumulates, causing a inavailable phosphate, which

results in inhibition ofglycogenolysis

and gluconeogenesis.


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findings

hypoglycemia, jaundice, cirrhosis,vomiting.


Tx

must intake of both fructose andsucrose (glucose + fructose).

Essential fructosuria

Involves a defect in fructokinaseand is a benign, asymptomatic

condition.Symptoms: fructose appears inblood and urine.

Involves a defect in fructokinaseand is a benign, asymptomatic

condition.fructose appears in blood and

urine.

Essential fructosuria

Galactosemia

mech

Absence of galactose-1-phosphate uridyltransferase.

Autosomal recessive. Damage iscaused by accumulation of toxicsubstances (including galactitol)

rather than absence

of an essential compound.

Galactosemia

clinical findings

cataracts, hepatosplenomegaly,mental retardation.

Galactosemia

Tx

exclude galactose and lactose(galactose + glucose) from diet.


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Amino acids

Ketogenic:Leu, Lys

Amino acids

Glucogenic/ketogenicIle, Phe, Trp

Amino acids

Glucogenic Met, Thr, Val, Arg, His

Amino acids

Essential

PVT. TIM HALL always argues,never tires":

Phe- Val- Thr- Trp- Ile- Met- His-Arg- Lue- Lys

Amino acids

AcidicAsp and Glu

Amino acids

Basic (and relative strengths)

Arg, Lys, and His.Arg is most basic.

His has no charge at body pH.

Hyperammonemia

who

Can be acquired (e.g., liverdisease) or hereditary

(e.g., ornithine transcarbamoylasedeficiency).


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66/112

Amino acid derivatives

Phenylalanine

from first to last

Tyrosine ^(Thyroxine)to

Dopamineto

Dopa ^(Melanin)toNEto

Epi


Tryptophan

-Niacin ^ (NAD+/NADP+)or

-Melatoninor

-Serotonin


HistidineHistamine


Glycineto Porphyrin to Heme


Arginine

UreaorNitric oxide

orCreatine


Glutamate

GABA (glutamate

decarboxylaserequires B6)


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What is the original amino acid for

NEThyroxine

Tyrosine Dopamine Dopa EpiMelanin

Phenylalanine


Niacin NAD+/NADP+MelatoninSerotonin

Tryptophan


HistamineHistidine

What is the original amino acid forPorphyrin Heme

Glycine


UreaNitric oxide

Creatine

Arginine


GABA (glutamatedecarboxylaserequires B6)

Glutamate

Normally, phenylalanine isconverted into tyrosine


68/112

Phenylketones

name the three

phenylacetate,phenyllactate, andphenylpyruvate.

Phenylketonuria

mech

there is phenylalaninehydroxylase or

tetrahydrobiopterin cofactor.Tyrosine becomes essential andphenylalanine builds up, leading

to excess phenylketones in urine.

Phenylketonuria

clinical findings

mental retardation, growthretardation, fair skin, eczema,

musty body odor.

Phenylketonuria

Tx

Treatment: phenylalanine(contained in

aspartame, e.g., NutraSweet) and

tyrosine in diet.

Alkaptonuriaaka

ochronosis

ochronosisaka

Alkaptonuria


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Alkaptonuria(ochronosis)

mech and findings

Congenital deficiency ofhomogentisic acid oxidase in the

degradative pathway oftyrosine. Resulting alkapton

bodies cause urine to turn blackon standing. Also, the

connective tissue is dark. Benigndisease. May have debilitating

arthralgias.

Albinism

causes

Congenital deficiency of either ofthe following:

1. Tyrosinase (inability tosynthesize melanin

from tyrosine)2. Defective tyrosine transporters

( amounts oftyrosine and thus melanin)

-Can result from a lack ofmigration of neural

crest cells.

Albinism

wrt inheritance

AR - Variable inheritance due tolocus heterogeneity.

Albinism

wrt risk

Lack of melanin results in an risk of skin cancer.


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Homocystinuria3 forms mech and Tx

1. Cystathionine synthasedeficiency (treatment:

Met and Cys in diet)2. affinity of cystathionine

synthase forpyridoxal phosphate (treatment:

vitaminB6 in diet)

3. Methionine synthase deficiency

Homocystinuriageneral mech

Results in excess homocysteinein the urine. Cysteinebecomes essential.

Homocystinuria

findings

Can cause mental retardation,osteoporosis, tall stature,kyphosis, lens subluxation

(downward and inward), andatherosclerosis (stroke and

MI).

Cystinuria

mech

Common (1:7000) inherited defectof renal tubular

amino acid transporter forCystine, Ornithine,

Lysine, and Arginine in kidneys.

COLA

Cystinuria clinical findings and Tx

Excess cystine in urine can leadto the precipitation

of cystine kidney stones.

Treat with acetazolamide toalkalinize the urine.


71/112

Maple syrup urine disease

mech

Blocked degradation of branchedamino acids

(Ile, Val, Leu) "I Love Vermontmaple syrup" due to -ketoacid

dehydrogenase.Causes -ketoacids in the blood,

especially Leu.

Maple syrup urine disease

clinical findings

Urine smells like maple syrup.

Causes severe CNS defects,mental retardation, and

death.

Lesch-Nyhan syndrome

mech

Purine salvage problem owing toabsence of HGPRTase. Resultsin excess uric acid production.

Lesch-Nyhan syndrome

findings

Findings: retardation, self-mutilation, aggression,

hyperuricemia, gout, andchoreoathetosis.

retardation, self-mutilation,aggression, hyperuricemia, gout,

and choreoathetosis.Lesch-Nyhan syndrome

Adenosine deaminase deficiency

mech

Excess ATP and dATPimbalances nucleotide pool via

feedback inhibition ofribonucleotide reductase. This

prevents DNA synthesis and thus lymphocyte count.


72/112

1st disease to be treated byexperimental

human gene therapy.Adenosine deaminase deficiency

Adenosine deaminase deficiency

complications

SCIDsevere combined(T and B) immunodeficiency

Liver: fed state vs.fasting state

what is released in fed statejust VLDL


what is released in fasting state

Glucoseand

Ketonebodies


mnemonic

In the PHasting state,PHosphorylate.

what cells don't need insulin touptake glucose

BRICK L:

BrainRBCs

IntestineCorneaKidneyLiver


73/112

Where are different GLUT'sand different activities

-GLUT1: RBCs, brain-GLUT2 (bidirectional): islet

cells, liver, kidney-GLUT4 (insulin responsive):

adipose tissue, skeletalmuscle

5 Anabolic effects of insulin:

1. glucose transport2. glycogen synthesis and

storage3. triglyceride synthesis and

storage4. Naretention (kidneys)

5. protein synthesis (muscles)

Serum C-peptide is not presentwith

exogenous insulin intake.

???? inhibits glucagonrelease by cells of pancreas.

insulin

Glycogen synthase

regulation in liver and muscle

Liver:Insulin and/or Glucose

-Glucagon and or Epinephrine

Muscle:Insulin

-Epinephrine


regulation in liver and muscle

LiverEpinephrine and or Glucagon

-Insulin

Muscle:AMP and/or epinephrine

-ATP and/or Insulin


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Required for adiposeand skeletal muscle uptake of

glucose.Insulin

Glycogen storage diseases

names of the main ones

"Very Poor CarbohydrateMetabolism"

Von Gierkes disease (Type I)

Pompes disease(Type II)

Coris disease(Type III)

McArdles disease (Type V)

Glycogen storage diseases

#'s and features

12 types, all resulting in abnormalglycogen metabolism and an

accumulation of glycogen withincells.

Von Gierkes disease

Findings, Deficient enzyme andcomments

Severe fasting hypoglycemia, glycogen in liver, bloodlactate, hepatomegaly.

Glucose-6-phosphate.

-The liver becomes a muscle.

(Think about it.)

Pompes disease


Cardiomegaly and systemicfindings leading to early death.

Lysosomal -1,4- glucosidase(acid maltase).

Pompes trashes the Pump (heart,liver, and muscle).


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Coris disease


Milder form of Type I with normalblood lactate levels.

Debranching enzyme-1,6-glucosidase.

McArdles disease


glycogen in muscle, but cannotbreak it down, leading to painfulmuscle cramps, myoglobinuria

with strenuous exercise.

Skeletal muscle glycogenphosphorylase.

glycogen in muscle, but cannotbreak it down, leading to painfulmuscle cramps, myoglobinuria

with strenuous exercise.

McArdles disease

Severe fasting hypoglycemia, glycogen in liver, bloodlactate, hepatomegaly.

Von Gierkes disease

Cardiomegaly and systemicfindings leading to early death.

Pompes disease

Inheritance of Lysosomal storagediseases

Fabrys disease and Hunterssyndrome are XR

the rest are AR


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Fabrys disease

Findings/Deficient enzyme

/Accumulated substrate

Peripheral neuropathy ofhands/feet, angiokeratomas,cardiovascular/renal disease

-galactosidase A

Ceramidetrihexoside

Gauchers disease

Findings

/Deficient enzyme/Accumulated substrate

Hepatosplenomegaly,aseptic necrosis of femur,

bone crises, Gauchers cells(macrophages)

-glucocerebrosidase

Glucocerebroside

Niemann-Pickdisease



"No man picks (Niemann-Pick)his nose with his sphinger

(sphingomyelinase)."

Progressive neurodegeneration,hepatosplenomegaly, cherry-

red spot (on macula)

Sphingomyelinase

Sphingomyelin

Tay-Sachs disease



Progressive neurodegeneration,developmental delay,

cherry-red spot, lysozymeswith onion skin

' Tay-SaX (Tay-Sachs)lacks heXosaminidase."

Hexosaminidase A

GM2 ganglioside


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Krabbes disease



Peripheral neuropathy,developmental delay,

optic atrophy

-galactosidase

Galactocerebroside

Metachromaticleukodystrophy



Central and peripheraldemyelination with ataxia,

dementia

Arylsulfatase A

Cerebroside sulfate

Hurlers syndrome



Developmental delay,gargoylism, airway obstruction,

corneal clouding,hepatosplenomegaly

-L-iduronidase

Heparan sulfate,dermatan sulfate

Hunters syndrome



Mild Hurlers + aggressivebehavior, no corneal

clouding

Iduronate sulfatase

Heparan sulfate,dermatan sulfate


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Lysosomal storage diseases

names and general classes

Sphingoliposes:Fabrys disease - Gauchers

disease - Niemann-Pick -Tay-Sachs disease - Krabbes

disease - Metachromaticleukodystrophy

Mucopolysaccharidoses:Hurlers syndrome -Hunters

syndrome

Lysosomal storage diseases

most common

Gauchers disease

Hepatosplenomegaly,aseptic necrosis of femur,

bone crises, Gauchers cells(macrophages)

Gauchers disease

Progressive neurodegeneration,hepatosplenomegaly, cherry-

red spot (on macula)

Niemann-Pickdisease

Tay-Sachs disease

Peripheral neuropathy ofhands/feet, angiokeratomas,cardiovascular/renal disease

Fabrys disease

inability to utilize LCFAsand toxic accumulation.

Carnitine deficiency:


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Ketone bodies

where/how/why produced

In liver: fatty acid and amino acids HMG-CoA acetoacetate +-hydroxybutyrate (to be used inmuscle and brain Ketone bodiesare metabolized by the brain to 2

molecules of

acetyl-CoA.)

Ketone bodies

when

prolonged starvation and diabeticketoacidosis


rate limiting step and mechand wrt esterificatoin

Rate-limiting step is catalyzed by

HMG-CoAreductase, which converts HMG-

CoA to mevalonate.23 of plasma cholesterol is

esterifiedby lecithin-cholesterol

acyltransferase (LCAT).

Lovastatin inhibitsHMG-

CoA reductase.

what inhibits HMG-CoA reductase.

statins

Essential fatty acids

and why

Linoeic and linolenic acids.Arachidonic acid, if linoleic acid is

absent.

Eicosanoids are dependent onessential fatty acids.


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Lipases (function/which one)

degradation of dietary TG in smallintestine.

Pancreatic lipase


Pancreatic lipase

degradation of dietary TG in smallintestine.


Lipoprotein lipase

degradation of TG circulating in

chylomicrons and VLDLs.


degradation of TG circulating inchylomicrons and VLDLs.

Lipoprotein lipase


Hepatic TG lipase

degradation of TG remaining inIDL.


degradation of TG remaining inIDL.

Hepatic TG lipase


Hormone-sensitive lipase

degradation of TG stored in

adipocytes.


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82/112


83/112

Major apolipoproteins

function of EMediates Extra (remnant) uptake.

Which lipoproteins are on

IDL

B-100

E


LDL B-100


VLDL

C-IIB-100

E


Chylomicron remnant

B-48E


Chylomicron

AB-48C-IIE

Lipoprotein

compositions

Lipoproteins are composed ofvarying proportions of cholesterol,

triglycerides,and phospholipids.


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carry most cholestero LDL and HDL

Function and route

Chylomicron

Delivers dietary triglycerides toperipheral tissues anddietary cholesterol to liver.

Secreted by intestinalepithelial cells.

Function and route

VLDL

Delivers hepatic triglycerides to

peripheral tissuesSecreted by liver.

Function and route

IDL

Formed in the degradation ofVLDL. Delivers triglycerides andcholesterol to liver, where they

are degraded to LDL.

Function and route

LDL

Delivers hepatic cholesterol toperipheral tissues.

Formed by lipoprotein lipasemodification of

VLDL in the peripheral tissue.Taken up by targe

cells via receptor-mediatedendocytosis.

Function and route

HDL

Mediates centripetal transport ofcholesterol (reverse cholesterol

transport, from periphery to liver).Acts as a repository for apoC and

apoE (which areneeded for chylomicron and VLDL

metabolism).Secreted from both liver and

intestine.


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Familial dyslipidemias

Type I

-aka-What is increased

-elevated blood levels-pathophys

Ihyperchylomicronemia

Chylomicrons

TG, cholesterol

Lipoprotein lipase deficiencyor altered apolipoprotein C-II


Type IIa



IIahypercholesterolemia

LDL

Cholesterol

LDL receptors


Type IV



IVhypertriglyceridemia

VLDL

TG

Hepatic overproduction of VLDL

Underproduction of heme causes

?

Accumulation ofintermediates causes ?

microcytic hypochromic anemia.

porphyrias.

Porphyrias

name them

Lead poisoning

Acute intermittent porphyria

Porphyria cutanea tarda


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Porphyrias

symptyoms

Symptoms = 5 Ps:Painful abdomen, Pink urine,

Polyneuropathy, Psychologicaldisturbances, Precipitated by

drugs

Affected enzyme andAccumulated substrate in urine

Lead poisoning

Ferrochelatase and ALAdehydrase

Coproporhyrin and ALA


Acute intermittent porphyria

porphobilinogen deaminase

Porphobilinogen and -ALA


Porphyria cutanea tarda

Uroporphyrinogen decarboxylase

Uroporphyrin (tea-colored)

Heme catabolism

scavanve mech

Heme is scavenged from RBCsand Fe2+ is reused. Heme

biliverdin bilirubin

what makes bruises blue/green biliverdin

Heme catabolism

wrt newborns

jaundiced newborns are put underUV light which converts bilirubin

into urine- solubile products


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Hemoglobin

formations and implications

1. T (taut) form has low affinity forO2.

2. R (relaxed) form has highaffinity for O2

(300).

Hemoglobin

wrt allosteric

Hemoglobin exhibits positivecooperativity and negativeallostery (accounts for the

sigmoid-shaped O2dissociation curve for

hemoglobin),unlike myoglobin.

how can fetal Hb take O2 from Hb

Fetal hemoglobin (2 and 2subunits) has lower affinity

for 2,3-BPG than adulthemoglobin (HbA) and thushas higher affinity for O2.

Cl, H+, CO2, 2,3-BPG, andtemperature shifts dissociationcurve to right, leading to O2

unloading)

HOW?

favor T form over R form

promoting O2 unloading (negativeallosteric regulation).

CO2 transport inblood by Hb (where)

CO2 (primarily as bicarbonate)binds to amino acids in globinchain at N terminus, but not

to heme.

cyanide poisoning

Tx and mech

Administer nitrites in cyanidepoisoning to oxidize hemoglobin

to methemoglobin.


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Methemoglobin

Oxidized form of hemoglobin(ferric, Fe3+) that does not bind

O2 as readily, but has affinity forCN.

Iron in hemoglobin is normallyin a reduced

state (ferrous, Fe2+).

Form of hemoglobin bound to CO

in place of O2.

Form of hemoglobin bound to CO

in place of O2.

Oxidized form of hemoglobin(ferric, Fe3+) that does not bind

O2 as readily, but has affinity forCN.

Carboxyhemoglobin

Methemoglobin

TxMethemoglobin

CO has a ?????? affinitythan O2 for hemoglobin.

Treat toxic levels ofMETHemoglobin with

METHylene blue.

Polymerase chainreaction (PCR)

steps

200 greater


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different direction blots

1. DNA is denatured by heating togenerate 2 separate strands

2. During cooling, excesspremade DNA primers anneal to a

specific sequence on eacstrand to be amplified

3. Heat-stable DNA polymerasereplicates the DNA sequence

following each primer

A rapid immunologic techniquetesting for antigen-antibody

reactivity.

SNoW DRoP:Southern = DNANorthern = RNA

Western = Protein

Enzyme-linkedimmunosorbentassay (ELISA)

why

Enzyme-linked immunosorbentassay (ELISA)

Fluorescence in situ hybridization(FISH)

to determinewhether a particularantibody (e.g., anti-HIV) ispresent in a patients bloodample. Both the sensitivity

Genetic terms

Variable expression

Fluorescent probe binds tospecific gene site of interest.

Specific localization of genes anddirect visualization of anomaliesat molecular level.

Genetic terms

Nature and severity of thephenotype varies from 1 individual

to another.

Nature and severity of thephenotype varies from 1 individual

to another.


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Genetic terms

Incomplete penetranceVariable expression

Genetic terms

Not all individuals with a mutantgenotype show the mutant

phenotype.

Not all individuals with a mutantgenotype show the mutant

phenotype.

Genetic terms

Pleiotropy Incomplete penetrance

Genetic terms

1 gene has > 1 effect on anindividuals phenotype.

1 gene has > 1 effect on anindividuals phenotype.

Genetic terms

ImprintingPleiotropy

Genetic terms

Differences in phenotype dependon whether the mutation is of

maternal or paternalorigin

Differences in phenotype depend

on whether the mutation is ofmaternal or paternal

origin (e.g., AngelMans syndrome[Maternal], Prader-Willi syndrome

[Paternal]).

Genetic terms

AnticipationImprinting


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Genetic terms

Tendency for certain alleles at 2linked loci to occur together more

often thanexpected by chance. Measured in

a population, not in a family, andoften varies in

different populations.

Tendency for certain alleles at 2linked loci to occur together more

often thanexpected by chance. Measured ina population, not in a family, and

often varies indifferent populations.

Genetic terms

MosaicismLinkage disequilibrium

Genetic terms

Occurs when cells in the bodyhave different genetic makeup

Occurs when cells in the bodyhave different genetic makeup

(e.g., lyonizationrandom X inactivation in females).

Genetic terms

Locus heterogeneityMosaicism

Genetic terms

Mutations at different loci canproduce the same phenotype

Mutations at different loci can

produce the same phenotype(e.g., albinism).

Hardy-Weinberg law assumes: Locus heterogeneity


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Imprinting

describe the main example

1. no mutation occurring at thelocus

2. There is no selection forany of the genotypes at the locus

3. random mating4. no migration

being considered

Prader-Willi

findings

Prader-Willi ( Deletion of normallyactive paternal allele)

Angelmans syndrome (Deletionof normally active maternal allele)

Angelmans syndrome

findings

Mental retardation, obesity,hypogonadism, hypotonia.

Mental retardation, seizures,ataxia, inappropriate laughter

(happy puppet).

Mental retardation, seizures,ataxia, inappropriate laughter

(happy puppet).

Mental retardation, obesity,hypogonadism, hypotonia.

Angelmans syndrome

Mitochondrial inheritance

diseasesPrader-Willi

Mitochondrial inheritance

mech

Lebers hereditary optic

neuropathy;

mitochondrialmyopathies.


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AR/AD/XR/XD

Von HippelLindaudisease

AD

AR/AD/XR/XD

Huntingtons diseaseAD

AR/AD/XR/XD

Familial adenomatouspolyposis

AD

AR/AD/XR/XD

Hereditaryspherocytosis

AD

AR/AD/XR/XD

AchondroplasiaAD

AR/AD/XR/XD

Cystic fibrosisAD

AR/AD/XR/XD

albinism

AR


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AR/AD/XR/XD

1-antitrypsin deficiencyAR

AR/AD/XR/XD

phenylketonuriaAR

AR/AD/XR/XD

thalassemias AR

AR/AD/XR/XD

sickle cell anemiasAR

AR/AD/XR/XD

glycogen storage diseasesAR

AR/AD/XR/XD

mucopolysaccharidosesAR

AR/AD/XR/XD

sphingolipidoses

AR

(except Hunters),


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AR/AD/XR/XD

infant polycystic kidney diseaseAR

AR/AD/XR/XD

hemochromatosisAR

AR/AD/XR/XD

Bruton's agammaglobulinemia

XR

Be Wise, Fool's GOLD HeedsFalse Hope.

AR/AD/XR/XD

Wiskott-Aldrich syndrome

XR


AR/AD/XR/XD

Fragile X

XR


AR/AD/XR/XD

G6PD deficiency

XR


AR/AD/XR/XD

Ocular albinism

XR



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Adult polycystic kidneydisease

presentation

Always bilateral, massiveenlargement of kidneys due tomultiple large cysts. Patientspresent with pain, hematuria,

hypertension, progressive renalfailure.


specific genetics

are due to mutation in APKD1(chromosome 16)

Adult polycystic kidney

disease

associations

Associated with polycystic liverdisease, berry aneurysms, mitral

valve prolapsediverticulosis

Familial hypercholesterolemia(hyperlipidemia type IIA)

clinical findings

severe atherosclerotic diseaseearly in life, and tendon

xanthomas (classically in theAchilles tendon); MI may develop

before age 20.

Familial hypercholesterolemia(hyperlipidemia type IIA)

lab findings

Elevated LDL owing to defectiveor absent LDL receptor.

Heterozygotes (1:500) havecholesterol 300 mg/dL.

Homozygotes (very rare) havecholesterol 700+ mg/dL,

Marfans syndrome

Skeletal abnormalities

tall with long extremities(arachnodactyly), pectus

excavatum, hyperextensive joints,and long, tapering fingers and

toes (see Image109).


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Marfans syndrome

vascular findings

Cardiovascularcystic medialnecrosis of aorta aortic

incompetence anddissecting aortic aneurysms.

Floppy mitral valve.

Marfans syndrome

ocular findingsOcularsubluxation of lenses.

Neurofibromatosis type 1

aka von Recklinghausens disease

von Recklinghausens diseaseaka

Neurofibromatosis type 1

Neurofibromatosistype 1 (von Recklinghausens

disease)

findings

caf-au-lait spots, neural tumors,Lisch nodules (pigmented irishamartomas). Also marked by

skeletal disorders (e.g., scoliosis),optic pathway

gliomas, pheochromocytoma, and

tumor susceptibility.

due to mutation in APKD1(chromosome 16)



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Tuberous sclerosis

findings

Findings: facial lesions (adenomasebaceum), hypopigmented ash

leaf spots on skin,cortical and retinal hamartomas,

seizures, mental retardation, renalcysts, cardiac

rhabdomyomas. Incompletepenetrance, variable presentation.

facial lesions (adenomasebaceum), hypopigmented ashleaf spots on skin, cortical andretinal hamartomas, seizures,

mental retardation, renal cysts,

cardiac rhabdomyomas.

Tuberous sclerosis


findings

hemangioblastomas ofretina/cerebellum/medulla; about

half of affectedindividuals develop multiple

bilateral renal cell carcinomas andother tumors.

hemangioblastomas ofretina/cerebellum/medulla; about

half of affectedindividuals develop multiple

bilateral renal cell carcinomas andother tumors.


Associated with deletion of VHLgene (tumor suppressor) on

chromosome 3 (3p).

Von HippelLindau = 3 words forchromosome 3.


specific genetics

Associated with deletion of VHLgene (tumor suppressor) on

chromosome 3 (3p).

Von HippelLindau = 3 words forchromosome 3.


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Huntingtons disease

clinical findings

Findings: depression, progressivedementia, choreiform movements,

Symptoms manifest in affectedindividuals between the ages of

20 and 50.

Huntingtons disease

lab/gross findings

caudate atrophy and levels ofGABA and ACh in the brain.

Huntingtons disease

specific genetics

Gene located on chromosome 4;

triplet repeat disorder. Hunting 4food.

Gene located on chromosome 4;triplet repeat disorder

Huntingtons disease

Hunting 4 food.


specific genetics

Colon becomes covered withadenomatous polyps after

puberty. Progresses to coloncancer unless resected.


findings

Deletion on chromosome 5; 5letters in polyp.

Deletion on chromosome 5


5 letters in polyp.


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findings

Spheroid erythrocytes; hemolyticanemia; increased MCHC.


Tx

Splenectomy is curative.

Achondroplasia

gene/mech

Autosomal-dominant cell-

signaling defect of fibroblastgrowth factor (FGF) receptor 3.

Achondroplasia

findings

Results in dwarfism; short limbs,but head and trunk are normal

size

Achondroplasia

associations

Associated with advancedpaternal age.

Cystic fibrosis

specific genetics

defect in CFTR gene onchromosome 7, commonly

deletion of Phe 508.

Cystic fibrosis

specific complication in males

Infertility in males due to absent

vas deferens.


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Most common lethal geneticdisease of Caucasians.

Cystic fibrosis

Treatment: N-acetylcysteineto loosen mucous plugs.

Cystic fibrosis

Cystic fibrosis

Tx

N-acetylcysteine to loosen

mucous plugs.

Cystic fibrosis

mech

Defective Cl channel secretionof abnormally thick mucus that

plugs lungs, pancreas, and liver recurrent pulmonary infections

What does the normal CFTRchannel do

CFTR channel secretes Cl inlungs and GI tract and reabsorbs

Cl from sweat.

Cystic fibrosis

Dx

concentrationof Cl ions in sweat test is

diagnostic.


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Cystic fibrosis

clinical findings

liver recurrent pulmonaryinfections (Pseudomonas speciesand S. aureus), chronic bronchitis,

bronchiectasis, pancreaticinsufficiency (malabsorption [Fat-

soluble

vitamin deficiencies (A, D, E,K] and steatorrhea),

meconium ileus in newborns.Infertility in males due to absentvas deferens. Can present as

failure tothrive in infancy.

recurrent pulmonary infections(Pseudomonas species and S.

aureus)Cystic fibrosis

Duchennes Muscular dystrophy

specific geneticsFrame-shift mutation deletionof dystrophin gene


mech

Frame-shift mutation deletionof dystrophin gene accelerated

muscle breakdown.


clinical findigns

gene accelerated musclebreakdown. Onset

before 5 years of age. Weaknessbegins in pelvic

girdle muscles and progressessuperiorly. Pseudohypertrophy of

calf muscles due to fibrofattyreplacement of muscle;

cardiac myopathy


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Mutated dystrophin gene is lesssevere thanDuchennes.

Beckers


Dx

Diagnose muscular dystrophiesby CPK and muscle biopsy.

Fragile X syndrome

specific genetics

X-linked defect affecting themethylation and expression of the

FMR1 gene. Triplet repeatdisorder (CGG)n that may showgenetic anticipation (germlike

expansion in females).

X-linked defect affecting themethylation and expression of the

FMR1 gene.Fragile X syndrome

The 2nd most common cause ofgenetic mental retardation

Fragile X syndrome

Fragile X syndrome

findings

-mental retardation-macro-orchidism (enlargedtestes)

-long face with a large jaw, -largeeverted ears,

-autism.


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-mental retardation-macro-orchidism (enlarged

testes)-long face with a large jaw, -large

everted ears,-autism.

Fragile X syndrome

Trinucleotide repeat expansiondiseases

name them

Huntingtons disease, myotonicdystrophy, Friedreichs ataxia,

fragile X syndrome.

"Try (trinucleotide) huntingfor my fried eggs (X)"

Autosomal trisomies

name them

Down syndrome

(trisomy 21),

Edwards syndrome(trisomy 18)

Pataus syndrome(trisomy 13)

Most common chromosomaldisorder

Down syndrome

Most common cause of congenitalmental retardation. Down syndrome


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Down syndrome

8 findings

1. mentalretardation,

2. flat facial profile,3. prominent epicanthal

folds,4. simian crease,

5. duodenal atresia,6. congenital heart disease

7. Alzheimers disease in affectedindividuals > 35 years old,

8. risk of ALL.

Down syndrome

what kind of heart defect

heart disease

(most common malformation isseptum primumtype ASD due toendocardial cushion defects),

Down syndrome

screening

levels of -fetoprotein,-hCG,

nuchal

translucency.

Down syndrome

mech/and mom age

95% of cases due to meioticnondisjunction of homologouschromosomes; associated with

advanced maternal age- 4% of cases due to robertsonian

translocation,

- 1% of cases due to Downmosaicism (no maternal

association)

Edwards syndrome

findings

severe mental retardation, rockerbottom feet, low-set ears,micrognathia (small jaw),congenital heart disease,

clenched hands,prominent occiput. Death usually

occurs within1 year of birth.


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severe mental retardation, rockerbottom feet, low-set ears,micrognathia (small jaw),congenital heart disease,

clenched hands,prominent occiput.

Edwards syndrome

Pataus syndrome

findings

severe mental retardation,microphthalm microcephaly, cleft

lip/palate, abnormal forebrainstructures, polydactyly, congenital

heart disease. Death usuallyoccurs within 1 year of birth.

severe mental retardation,

microphthalm microcephaly, cleftlip/palate, abnormal forebrain

structures, polydactyly, congenitalheart disease. Death usuallyoccurs within 1 year of birth.

Pataus syndrome

Congenital deletion of short arm

of chromosome 5(46,XX or XY, 5p).

Cri-du-chatsyndrome

Cri-du-chat syndrome

genetics

Congenital deletion of short armof chromosome 5

(46,XX or XY, 5p).


findings

microcephaly, severe mentalretardation, high-pitched

crying/mewing, epicanthal folds,cardiac abnormalities.


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microcephaly, severe mentalretardation, high-pitched

crying/mewing, epicanthal folds,cardiac abnormalities.


22q11 syndrome

main

CATCH-22.

Cleft palate,Abnormal facies,Thymic aplasia T-cell deficiency, C

ardiac defects,Hypocalcemia

2 to parathyroid aplasia,microdeletion at

chromosome 22q11. Variablepresentation as

22q11 syndromes

Variable presentation as

DiGeorge syndrome (thymic,parathyroid, and cardiac defects)

or velocardiofacial syndrome

(palate, facial, and cardiacdefects).

Fetal alcohol syndrome

worst window38 weeks

Fetal alcohol syndrome

complications

-pre- and postnatal developmentalretardation, -microcephaly,

-facial abnormalities,-limb dislocation,

-heart and lung fistulas.M

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