06/27/2017

usmle step 1 exam guide

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83

Rough RER is the site of synthesis of secretory (exported) Mucus-secreting goblet cells of

endoplasmic proteins and of N-linked oligosaccharide addition the small intestine and

reticulum (RER) to many proteins. antibody-secreting plasma

cells are rich in RER.

Nissl bodies Nissl bodies (in neurons)–rough ER; not found in axon or axon hillock.

Synthesize enzymes (e.g., ChAT) and peptide neurotransmitters.

Smooth SER is the site of steroid synthesis and detoxification Liver hepatocytes and

endoplasmic of drugs and poisons. steroid hormone-producing

reticulum (SER) cells of the adrenal cortex

are rich in SER.

Functions of Golgi 1. Distribution center of proteins and lipids from I-cell disease is caused by the

apparatus ER to the plasma membrane, lysosomes, and failure of addition of

secretory vesicles mannose-6-phosphate to

2. Modifies N-oligosaccharides on asparagine lysosome proteins, causing

3. Adds O-oligosaccharides to serine and threonine these enzymes to be secreted

residues outside the cell instead of

4. Proteoglycan assembly from proteoglycan core being targeted to the

proteins lysosome. Characterized by

5. Sulfation of sugars in proteoglycans and of coarse facial features and

selected tyrosine on proteins restricted joint movement.

6. Addition of mannose-6-phosphate to specific

lysosomal proteins, which targets the protein

to the lysosome

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

RER

SER

Cell

membrane

Cell

membrane

trans

face

cis

face

(Reproduced, with permission, from Junqueira L, Carneiro J. Basic Histology, 10th ed.

New York:McGraw-Hill, 2003.)

BIOCHEMISTRY-CELLULAR (continued)

Microtubule Cylindrical structure 24 nm in diameter and of variable Drugs that act on microtubules:

length. A helical array of polymerized dimers of a- 1. Mebendazole/thiabendazole

and ß-tubulin (13 per circumference). Each dimer (antihelminthic)

has 2 GTP bound. Incorporated into flagella, cilia, 2. Taxol (anti-breast cancer)

mitotic spindles. Grows slowly, collapses quickly. 3. Griseofulvin (antifungal)

Microtubules are also involved in slow axoplasmic 4. Vincristine/vinblastine

transport in neurons. (anti-cancer)

5. Colchicine (anti-gout)

Chédiak-Higashi syndrome

is due to a microtubule

polymerization defect

resulting in . phagocytosis.

Cilia structure 9 + 2 arrangement of microtubules. Kartagener’s syndrome is due

Dynein is an ATPase that links peripheral to a dynein arm defect,

9 doublets and causes bending of cilium by resulting in immotile cilia.

differential sliding of doublets. Dynein = retrograde.

Kinesin = anterograde.

Plasma membrane Plasma membranes contain cholesterol (˜ 50%, promotes membrane stability),

composition phospholipids (˜ 50%), sphingolipids, glycolipids, and proteins. High cholesterol or

long saturated fatty acid content . . melting temperature. Only noncytoplasmic side

of membrane contains glycosylated lipids or proteins (i.e., the plasma membrane is an

asymmetric, fluid bilayer).

Phosphatidylcholine Phosphatidylcholine (lecithin) is a major component of RBC membranes, of myelin, of

function bile, and of surfactant (DPPC–dipalmitoyl phosphatidylcholine). Also used in

esterification of cholesterol (LCAT is lecithin-cholesterol acyltransferase).

Sodium pump Na+-K+ATPase is located in the plasma membrane Ouabain inhibits by binding to

with ATP site on cytoplasmic side. For each ATP K+ site. Cardiac glycosides

consumed, 3 Na+ go out and 2 K+ come in. (digoxin, digitoxin) also

During cycle, pump is phosphorylated. inhibit the Na+-K+ATPase,

causing . cardiac contractility.

84 BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

24 nm

Microtubule

doublets

Dynein ATPase

Cytosolic

side 3Na+ ATP

ADP

3Na+ 2K+

2K+

Extracellular

side

P

P

G-protein-linked 2nd messengers

Receptor G-protein class

HAVe 1M&M.

MAD 2s.

Collagen types Collagen is the most abundant protein in the Be Cool, Read Books.

human body. Functions to organize and

strengthen extracellular matrix.

Type I (90%)–Bone, tendon, skin, dentin, fascia, Type I: BONE.

cornea, late wound repair.

Type II–Cartilage (including hyaline), vitreous Type II: carTWOlage.

body, nucleus pulposus.

Type III (Reticulin)–skin, blood vessels, uterus,

fetal tissue, granulation tissue.

Type IV–Basement membrane or basal lamina. Type IV: Under the floor

Type X–epiphyseal plate. (basement membrane).

Collagen synthesis Inside fibroblasts:

and structure 1. Collagen a chains (preprocollagen)

translated on RER–usually Gly-X-Y

polypeptide (X and Y are proline,

hydroxyproline, or hydroxylysine)

2. ER .hydroxylation of specific proline

and lysine residues (requires vitamin C)

3. Golgi .glycosylation of pro-a-chain

lysine residues and formation of

procollagen (triple helix of 3 collagen

a chains)

4. Procollagen molecules are exocytosed

into extracellular space

Outside fibroblasts:

5. Procollagen peptidases cleave terminal

regions of procollagen, transforming

procollagen into insoluble tropocollagen

6. Many staggered tropocollagen molecules

are reinforced by covalent lysine-hydroxylysine

cross-linkage (by lysyl oxidase) to make collagen

fibrils

85

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

Receptor

Lipids

PIP2

H1, a1, V1, Gq

M1, M3

IP3 [Ca2+]in

DAG Protein

kinase C

Phospholipase C

Gs

ß1, ß2, D1,

H2, V2

Protein kinase A

ATP

cAMP

Receptor

Adenylyl cyclase

M2, a2, D2

Gi

Receptor

+

mRNA

Nucleus

Glycosylation

(pro a chain)

Triple helix (procollagen)

Osteogenesis

imperfecta

Collagen fibrils

with crosslinks

OH OH

OH OH

ER

DNA

Golgi

Ehlers-Danlos

Scurvy

Hydroxylation

Cell membrane

Peptide cleavage

c(1-)

86

BIOCHEMISTRY-CELLULAR (continued)

Ehlers-Danlos Faulty collagen synthesis causing:

syndrome 1. Hyperextensible skin

2. Tendency to bleed (easy bruising)

3. Hypermobile joints

10 types. Inheritance varies. Associated with berry aneurysms.

Osteogenesis Primarily an autosomal-dominant disorder caused May be confused with child

imperfecta by a variety of gene defects, resulting in abnormal abuse.

collagen synthesis. Clinically characterized by: Type II is fatal in utero and in

1. Multiple fractures occurring with minimal the neonatal period.

trauma (brittle bone disease), which may Incidence is 1:10,000.

occur during the birth process

2. Blue sclerae due to the translucency of the

connective tissue over the choroid

3. Hearing loss (abnormal middle ear bones)

4. Dental imperfections due to lack of dentition

Immunohistochemical stains

Stain Cell type

Vimentin Connective tissue

Desmin Muscle

Cytokeratin Epithelial cells

Glial fibrillary acid proteins (GFAP) Neuroglia

Neurofilaments Neurons

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

BIOCHEMISTRY-METABOLISM

Metabolism sites

Mitochondria Fatty acid oxidation (ß-oxidation), acetyl-CoA production, Krebs cycle.

Cytoplasm Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis

(SER).

Both Gluconeogenesis, urea cycle, heme synthesis.

Summary of pathways

87

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

Glycogen

UDP-glucose Glucose-1-phosphate

Glucose

Glucose-6-phosphate 6-phosphogluconolactone

Fructose-6-phosphate

Fructose-1,6-bisphosphate

Glyceraldehyde-3-P DHAP

1,3-bis-phosphoglycerate

3-phosphoglycerate

2-phosphoglycerate

Phosphoenolpyruvate (PEP)

Pyruvate

Acetyl-CoA

Glyceraldehyde

Ribulose-5-phosphate

F1P Fructose

NH4 + CO2

Carbamoyl

phosphate

Citrulline

Aspartate

Argininosuccinate

Urea

cycle

Ornithine

Urea

H2O

Arginine

Fumarate

Oxaloacetate

Malate TCA

cycle

Succinate

Citrate

Isocitrate

a-ketoglutarate

Succinyl-CoA Methylmalonyl-CoA

Propionyl-CoA

Odd-chain

fatty acids

Acetoacetate ß-hydroxybutyrate

Mevalonate

Galactose

Galactose-1-phosphate

HMP shunt

Glycolysis

Lactate

Acetoacetyl-CoA HMG-CoA

Malonyl-CoA Fatty acids

Cholesterol

1

2 3 4

5

6

7 8

9

11

Gluconeogenesis 12

15

14

16

17

18

10

1 Galactokinase (mild galactosemia)

2 Galactose-1-phosphate uridyltransferase

(severe galactosemia)

3 Hexokinase/glucokinase

4 Glucose-6-phosphatase (von Gierke’s)

5 Glucose-6-phosphate dehydrogenase (G6PD)

6 Transketolase

7 Phosphofructokinase

8 Fructose-1,6-bisphosphatase

9 Fructokinase (essential fructosuria)

10 Aldolase B (fructose intolerance)

11 Pyruvate kinase

12 Pyruvate dehydrogenase

13 HMG-CoA reductase

14 Pyruvate carboxylase

15 PEP carboxykinase

16 Citrate synthase

17 a-ketoglutarate dehydrogenase

18 Ornithine transcarbamylase

13

88

BIOCHEMISTRY-METABOLISM (continued)

ATP Base (adenine), ribose, 3 phosphoryls. 2 phosphoanhydride bonds, 7 kcal/mol each.

Aerobic metabolism of glucose produces 38 ATP via malate shuttle, 36 ATP via G3P shuttle.

Anaerobic glycolysis produces only 2 net ATP per glucose molecule.

ATP hydrolysis can be coupled to energetically unfavorable reactions.

Activated carriers Phosphoryl (ATP).

Electrons (NADH, NADPH, FADH2).

Acyl (coenzyme A, lipoamide).

CO2 (biotin).

1-carbon units (tetrahydrofolates).

CH3 groups (SAM).

Aldehydes (TPP).

Glucose (UDP-glucose).

Choline (CDP-choline).

S-adenosyl- ATP + methionine . SAM. SAM transfers methyl SAM the methyl donor man.

methionine units to a wide variety of acceptors (e.g., in

synthesis of phosphocreatine, a high-energy

phosphate active in muscle ATP production).

Regeneration of methionine (and thus SAM) is

dependent on vitamin B12.

Signal molecule ATP . cAMP via adenylate cyclase.

precursors GTP . cGMP via guanylate cyclase.

Glutamate . GABA via glutamate decarboxylase (requires vitamin B6).

Choline . ACh via choline acetyltransferase (ChAT).

Arachidonate . prostaglandins, thromboxanes, leukotrienes via cyclooxygenase/

lipoxygenase.

Fructose-6-P . fructose-1,6-bis-P via phosphofructokinase (PFK), the rate-limiting

enzyme of glycolysis.

1,3-BPG . 2,3-BPG via bisphosphoglycerate mutase.

Universal electron Nicotinamides (NAD+, NADP+) and flavin NADPH is a product of the

acceptors nucleotides (FAD+). HMP shunt.

NAD+ is generally used in catabolic processes to

carry reducing equivalents away as NADH.

NADPH is used in anabolic processes (steroid NADPH is used in:

and fatty acid synthesis) as a supply of reducing 1. Anabolic processes

equivalents. 2. Respiratory burst

3. P-450

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

NH2

O O O -O P P P

HO HO

N

N N

N

O

O O O

O- O- O-

~ ~

89

Oxygen-dependent respiratory burst

Hexokinase vs. Hexokinase is found throughout body. Only hexokinase is feedback

glucokinase GLucokinase is primarily found in the Liver inhibited by G6P.

(lower affinity [. Km] but higher capacity Glucokinase phosphorylates

[. Vmax]). excess glucose (e.g., after a

meal) to sequester it in the

liver as G6P.

Glycolysis D-glucose Glucose-6-phosphate Glucose-6-P [1].

regulation, Hexokinase/glucokinase*

irreversible Fructose-6-P Fructose-1,6-BP ATP [1], AMP ., citrate [1],

enzymes Phosphofructokinase-1 fructose-2,6-BP ..

(rate-limiting step)

Phosphoenolpyruvate Pyruvate ATP [1], alanine [1],

Pyruvate kinase fructose-1,6-BP ..

Pyruvate Acetyl-CoA ATP [1], NADH [1],

Pyruvate acetyl-CoA [1].

dehydrogenase

* Glucokinase in liver; hexokinase in all other tissues.

Glycolytic enzyme Hexokinase, glucose phosphate isomerase, aldolase, RBCs metabolize glucose

deficiency triosephosphate isomerase, phosphate glycerate anaerobically (no

kinase, enolase, and pyruvate kinase deficiencies mitochondria) and thus

are associated with hemolytic anemia. depend solely on glycolysis.

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

Phagolysosome

Neutrophil

cell membrane

O2

.

O2

.

H2O2

.

HOCl•

.

NADPH

NADP+

H2O2 H2O

GSH GSSG

NADP+ NADPH

G6P 6PG

Cl-

GSH/GSSG = glutathione

(reduced/oxidized)

HOCl• = bleach

Bacteria

1 NADPH oxidase (deficiency =

chronic granulomatous disease)

2 Superoxide dismutase

3 Myeloperoxidase

4 Catalase

5 Glutathione reductase

6 Glucose-6-phosphate

dehydrogenase (G6PD)

1

2

3

4

5

6

BIOCHEMISTRY-METABOLISM (continued)

Pyruvate The complex contains 3 enzymes that require 5 The complex is similar to the

dehydrogenase cofactors (the first 4 B vitamins plus lipoic acid): a-ketoglutarate

complex 1. Pyrophosphate (B1, thiamine; TPP) dehydrogenase complex

2. FAD (B2, riboflavin) (same cofactors, similar

3. NAD (B3, niacin) substrate and action).

4. CoA (B5, pantothenate)

5. Lipoic acid

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

CO2 + NADH.

Activated by exercise:

. NAD+/NADH ratio

. ADP

. Ca2+

Pyruvate Causes backup of substrate (pyruvate and alanine), Lysine and Leucine–the only

dehydrogenase resulting in lactic acidosis. Can be seen in purely ketogenic amino

deficiency alcoholics due to B1 deficiency. acids.

Findings: neurologic defects.

Treatment: . intake of ketogenic nutrients (e.g., high

fat content or . lysine and leucine).

Pyruvate metabolism 6 ATP equivalents are needed

to generate glucose from

pyruvate.

Alanine serves as carrier of

amino groups from muscle to

liver.

Oxaloacetate can be used to

replenish TCA cycle or in

gluconeogenesis.

Cori cycle Transfers excess reducing

equivalents from RBCs and

muscle to liver, allowing

muscle to function

anaerobically (net 2 ATP).

90 BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

MUSCLE LIVER

BL

OOD

Glucose

2ATP

Pyruvate

Lactate

dehydrogenase

Lactate

Pyruvate

Lactate

Lactate

dehydrogenase

6ATP

Glucose

Lactate

Glucose

Cytosol

Mitochondria

Alanine

NADH + H+ NAD+

NADH + H+

Oxaloacetate Acetyl-CoA

CO NAD+ 2 + ATP

CO2

Pyruvate ALT LDH

PC

PDH

91

TCA cycle Produces 3 NADH, 1 FADH2,

2 CO2, 1 GTP per acetyl-

CoA = 12 ATP/acetyl-CoA

(2× everything per glucose)

a-ketoglutarate dehydrogenase

complex requires same

cofactors as the pyruvate

dehydrogenase complex.

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Electron transport chain and oxidative phosphorylation

Electron transport 1 NADH . 3 ATP; 1 FADH2 . 2 ATP.

chain

Oxidative 1. Electron transport inhibitors (rotenone, antimycin A, CN-, CO) directly inhibit

phosphorylation electron transport, causing a . of proton gradient and block of ATP synthesis.

poisons 2. ATPase inhibitor (oligomycin) directly inhibits mitochondrial ATPase, causing an

. of proton gradient, but no ATP is produced because electron transport stops.

3. Uncoupling agents (2,4-DNP) . permeability of membrane, causing a . of

proton gradient and . O2 consumption. ATP synthesis stops. Electron transport

continues.

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

Acetyl-CoA

NADH

Malate

Fumarate

Succinate

Succinyl-

CoA

CO2 + NADH

a-ketoglutarate

Isocitrate

cis-aconitate

Citrate Citrate

synthase

Isocitrate

dehydrogenase

a-KG

GTP dehydrogenase

+

CoA

FADH2

Oxaloacetate

Pyruvate

Pyruvate

dehydrogenase

Succinyl-CoA

NADH

ATP

ATP

NADH

ADP

-+

ATP

Acetyl-CoA

NADH

– –

– ATP

CO2 + NADH

Oligomycin

Complex I Complex III Complex IV Complex V

ADP + Pi

NADH

ATP + H2O

2,4-Dinitrophenol

NAD+

H+ H+ H+ H+

CoQ CoQ

1/2O2 H2O

BIOCHEMISTRY-METABOLISM (continued)

Gluconeogenesis, irreversible enzymes

Pyruvate carboxylase In mitochondria. Pyruvate . oxaloacetate. Requires biotin, ATP.

Activated by acetyl-CoA.

PEP carboxykinase In cytosol. Oxaloacetate . phosphoenolpyruvate. Requires GTP.

Fructose-1,6- In cytosol. Fructose-1,6-bisphosphate .

bisphosphatase fructose-6-P.

Pathway Produces

Glucose-6- In cytosol. Glucose-6-P . glucose. Fresh Glucose.

phosphatase

Above enzymes found only in liver, kidney, intestinal epithelium. Muscle cannot

participate in gluconeogenesis.

Hypoglycemia is caused by a deficiency of the key gluconeogenic enzymes listed above

(e.g., von Gierke’s disease, which is caused by a lack of glucose-6-phosphatase in the liver).

Pentose phosphate Produces ribose-5-P from G6P for nucleotide synthesis.

pathway (HMP Produces NADPH from NADP+ for fatty acid and steroid biosynthesis and for

shunt) maintaining reduced glutathione inside RBCs.

All reactions of this pathway occur in the cytoplasm. No ATP is used or produced.

Sites: lactating mammary glands, liver, adrenal cortex–all sites of fatty acid or steroid

synthesis.

Glucose-6- G6PD is a rate-limiting enzyme in HMP shunt G6PD deficiency is more

phosphate (which yields NADPH). NADPH is necessary prevalent among blacks.

dehydrogenase to keep glutathione reduced, which in turn Heinz bodies–altered

deficiency detoxifies free radicals and peroxides. . NADPH Hemoglobin precipitates

in RBCs leads to hemolytic anemia due to poor within RBCs.

RBC defense against oxidizing agents (fava beans, X-linked recessive disorder.

sulfonamides, primaquine) and antituberculosis

drugs.

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

NADP+ 2 GSH

(reduced)

GS-SG

(oxidized)

NADPH

Glutathione

reductase

Glucose-6-phosphate

dehydrogenase

G6P

6PG 2H2O

H2O2

92

Disorders of fructose metabolism

Fructose intolerance Hereditary deficiency of aldolase B (recessive). Fructose-1-phosphate accumulates,

causing a . in available phosphate, which results in inhibition of glycogenolysis

and gluconeogenesis.

Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting.

Treatment: must . intake of both fructose and sucrose (glucose + fructose).

Essential fructosuria Involves a defect in fructokinase and is a benign, asymptomatic condition.

Symptoms: fructose appears in blood and urine.

Disorders of galactose metabolism

Galactosemia Absence of galactose-1-phosphate uridyltransferase. Autosomal recessive. Damage is

caused by accumulation of toxic substances (including galactitol) rather than absence

of an essential compound.

Symptoms: cataracts, hepatosplenomegaly, mental retardation.

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

Galactokinase Causes galactosemia and galactosuria, galactitol accumulation if galactose is present in diet.

deficiency

Lactase deficiency Age-dependent and/or hereditary lactose intolerance (blacks, Asians).

Symptoms: bloating, cramps, osmotic diarrhea.

Treatment: avoid milk or add lactase pills to diet.

Essential amino Ketogenic: Leu, Lys. All essential amino acids:

acids Glucogenic/ketogenic: Ile, Phe, Trp. PriVaTe TIM HALL.

Glucogenic: Met, Thr, Val, Arg, His. Arg and His are required

during periods of growth.

FRUCTOSE METABOLISM (LIVER)

Fructose Fructose-1-P

Fructokinase Aldolase B

Dihydroxyacetone-P

Glyceraldehyde

Glyceraldehyde-3-P Glycolysis

Glycerol

Deficiency = fructose intolerance

  • Deficiency = essential fructosuria

NADH

Triose

kinase

ATP

ADP ATP

ADP

NAD

93

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

GALACTOSE METABOLISM

Galactose Galactose-1-P

Galactokinase

Aldose

reductase

Galactitol

Uridyl transferase

Glycolysis/

4-epimerase gluconeogenesis

Glucose-1-P

ATP

ADP UDP-Glu UDP-Gal

94

BIOCHEMISTRY-METABOLISM (continued)

Acidic and basic At body pH (7.4), acidic amino acids Asp and Glu Asp = aspartic ACID, Glu =

amino acids are negatively charged; basic amino acids Arg glutamic ACID.

and Lys are positively charged. Basic amino Arg and Lys have an extra

acid His at pH 7.4 has no net charge. NH3 group.

Arginine is the most basic amino acid. Arg and Lys

are found in high amounts in histones, which

bind to negatively charged DNA.

Transport of ammonium by alanine and glutamine

Urea cycle Degrades amino acids into amino groups. Accounts Ordinarily, Careless Crappers

for 90% of nitrogen in urine. Urea cycle occurs Are Also Frivolous About

in the liver; carbamoyl phosphate incorporation Urination.

occurs in the mitochondria; the remaining steps

occur in the cytosol.

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

CO2 + NH4

+

Carbamoyl

phosphate

Mitochondria

Cytoplasm

(Liver)

Citrulline

Ornithine

Arginine Fumarate

Argininosuccinate

Aspartate

Urea

H2O

Amino acids

(NH3)

(NH3)

a-ketoacids

a-ketoglutarate

Glutamate

Alanine

Pyruvate

Glucose

Alanine

Pyruvate

Glucose

a-ketoglutarate

Glutamate

Urea

Muscle Liver

Glutamine

NH4

+ NH4

+

Glutamate

NAD(P)+ NAD(P)H

a-ketoglutarate

(NH3) (NH3)

(NH3)

(NH3)

95

Amino acid derivatives

Phenylketonuria Normally, phenylalanine is converted into tyrosine Screened for at birth.

(nonessential aa). In PKU, there is . phenylalanine Phenylketones–phenylacetate,

hydroxylase or . tetrahydrobiopterin cofactor. phenyllactate, and

Tyrosine becomes essential and phenylalanine phenylpyruvate.

builds up, leading to excess phenylketones in urine. Autosomal-recessive disease.

Findings: mental retardation, growth retardation, Incidence ˜ 1:10,000.

fair skin, eczema, musty body odor. Disorder of aromatic amino

Treatment: . phenylalanine (contained in acid metabolism . musty

aspartame, e.g., NutraSweet) and . tyrosine in diet. body odor.

Alkaptonuria Congenital deficiency of homogentisic acid oxidase in the degradative pathway of

tyrosine. Resulting alkapton bodies cause urine to turn black on standing. Also, the

connective tissue is dark. Benign disease. May have debilitating arthralgias.

Albinism Congenital deficiency of either of the following: Lack of melanin results in an

1. Tyrosinase (inability to synthesize melanin . risk of skin cancer.

from tyrosine)

2. Defective tyrosine transporters (. amounts of

tyrosine and thus melanin)

Can result from a lack of migration of neural

crest cells.

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

Tryptophan

Niacin NAD+/NADP+

Melatonin

Serotonin

Phenylalanine NE

Thyroxine

Tyrosine Dopa Dopamine

Histidine Histamine

Glycine Porphyrin Heme

Epi

Arginine

Urea

Nitric oxide

Creatine

Melanin

Glutamate GABA

Phenylalanine

THB DHB

NADP+ NADPH

Phenylalanine

hydroxylase

Dihydropterin

reductase

Tyrosine

96

BIOCHEMISTRY-METABOLISM (continued)

Homocystinuria 3 forms: Results in excess homocysteine

1. Cystathionine synthase deficiency (treatment: in the urine. Cysteine

. Met and . Cys in diet) becomes essential.

2. . affinity of cystathionine synthase for Can cause mental retardation,

pyridoxal phosphate (treatment: .. vitamin osteoporosis, tall stature,

B6 in diet) kyphosis, lens subluxation

3. Methionine synthase deficiency (downward and inward), and

atherosclerosis (stroke and

MI).

Cystinuria Common (1:7000) inherited defect of renal tubular COLA.

amino acid transporter for Cystine, Ornithine, Treat with acetazolamide to

Lysine, and Arginine in kidneys. Excess cystine alkalinize the urine.

in urine can lead to the precipitation of cystine

kidney stones.

Maple syrup urine Blocked degradation of branched amino acids Urine smells like maple syrup.

disease (Ile, Val, Leu) due to . a-ketoacid dehydrogenase. I Love Vermont maple syrup.

Causes . a-ketoacids in the blood, especially Leu.

Causes severe CNS defects, mental retardation, and

death.

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

Methionine Homocysteine

THF CH3 THF

Methionine

synthase

Cystathionine

synthase

Cystathionine Cysteine

B12

B6

via SAM

CH3

97

Purine salvage deficiencies

Adenosine ADA deficiency can cause SCID. Excess ATP and SCID–severe combined

deaminase dATP imbalances nucleotide pool via feedback (T and B) immunodeficiency

deficiency inhibition of ribonucleotide reductase. This disease. SCID happens to

prevents DNA synthesis and thus . lymphocyte kids (remember “bubble

count. 1st disease to be treated by experimental boy”).

human gene therapy.

Lesch-Nyhan Purine salvage problem owing to absence of LNS–Lacks Nucleotide

syndrome HGPRTase, which converts hypoxanthine to Salvage (purine).

inosine monophosphate (IMP) and guanine to

guanosine monophosphate (GMP). X-linked

recessive. Results in excess uric acid production.

Findings: retardation, self-mutilation, aggression,

hyperuricemia, gout, and choreoathetosis.

Liver: fed state vs.

fasting state

In the PHasting state,

PHosphorylate.

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

Nucleic acids

Guanylic acid

(GMP)

Guanosine

Guanine

Inosinic acid

(IMP)

Hypoxanthine

Inosine Adenosine

Adenylic acid

(AMP)

Adenine

Nucleic acids

Xanthine

Uric acid

2

4

1

3

1 HGPRT + PRPP

2 APRT + PRPP

3 Adenosine deaminase (ADA)

1

4

4 Xanthine oxidase

VLDL

HMP

shunt TCA

cycle

FED STATE FASTING STATE

Digestive system

Glucose Amino Chylomicrons

acids

Fatty

acids

Amino acids

glycerol

lactate

Glycogen

G6P Pyruvate Acetyl-CoA

Glu

Ketone

bodies

Fats

Glu

Glu-6-P

Glycogen

Glycolysis /

TCA cycle

CM

Fatty

Protein acids

Glucose

AA

98

BIOCHEMISTRY-METABOLISM (continued)

Insulin Made in ß cells of pancreas. Required for adipose Insulin moves glucose Into cells.

and skeletal muscle uptake of glucose. BRICK L (don’t need insulin

GLUT2 receptors are found in ß cells and GLUT4 for glucose uptake):

in muscle and fat. Insulin inhibits glucagon Brain

release by a cells of pancreas. RBCs

Serum C-peptide is not present with exogenous Intestine

insulin intake. Cornea

Anabolic effects of insulin: Kidney

1. . glucose transport Liver

2. . glycogen synthesis and storage

3. . triglyceride synthesis and storage

4. . Na retention (kidneys)

5. . protein synthesis (muscles)

Insulin vs. Glucagon phosphorylates stuff . turns glycogen synthase OFF and phosphorylase ON.

glucagon Insulin dephosphorylates stuff . turns glycogen synthase ON and phosphorylase OFF.

Glycogen storage 12 types, all resulting in abnormal glycogen metabolism and an accumulation of glycogen

diseases within cells.

Type I Von Gierke’s disease–glucose-6-phosphatase The liver becomes a muscle.

deficiency. (Think about it.)

Findings: severe fasting hypoglycemia, .. glycogen

in liver, hepatomegaly, . blood lactate.

Type II Pompe’s disease–lysosomal a-1,4-glucosidase Pompe’s trashes the Pump

deficiency. (heart, liver, and muscle).

Findings: cardiomegaly and systemic findings, leading

to early death.

Type III Cori’s disease–deficiency of debranching enzyme

a-1,6-glucosidase.

Findings: milder form of type I with normal blood

lactate levels.

Type V McArdle’s disease–skeletal muscle glycogen McArdle’s: Muscle.

phosphorylase deficiency.

Findings: . glycogen in muscle but cannot break it Very Poor Carbohydrate

down, leading to painful cramps, myoglobinuria Metabolism.

with strenuous exercise.

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

C peptide

S S -COOH

Human proinsulin

NH2- a chain

ß chain

Cys Cys

Cys

S

S

Cys

Cys

S

S

Cys

99

Lysosomal storage Each is caused by a deficiency in one of the many lysosomal enzymes.

diseases

Accumulated

Disease Findings Deficient enzyme substrate Inheritance

Fabry’s disease Peripheral neuropathy of a-galactosidase A Ceramide XR

hands/feet, angiokeratomas, trihexoside

cardiovascular/renal disease

Gaucher’s disease Hepatosplenomegaly, ß-glucocerebrosidase Glucocerebroside AR

aseptic necrosis of femur,

bone crises, Gaucher’s cells

(macrophages)

Niemann-Pick Progressive neurodegeneration, Sphingomyelinase Sphingomyelin AR

disease hepatosplenomegaly, cherryred

spot (on macula)

Tay-Sachs disease Progressive neurodegeneration, Hexosaminidase A GM2 ganglioside AR

developmental delay,

cherry-red spot, lysozymes

with onion skin

Krabbe’s disease Peripheral neuropathy, ß-galactosidase Galactocerebroside AR

developmental delay,

optic atrophy

Metachromatic Central and peripheral Arylsulfatase A Cerebroside sulfate AR

leukodystrophy demyelination with ataxia,

dementia

Hurler’s syndrome Developmental delay, a-L-iduronidase Heparan sulfate, AR

gargoylism, airway dermatan sulfate

obstruction, corneal

clouding,

hepatosplenomegaly

Hunter’s syndrome Mild Hurler’s + aggressive Iduronate sulfatase Heparan sulfate, XR

behavior, no corneal dermatan sulfate

clouding

No man picks (Niemann-Pick)

his nose with his sphinger

(sphingomyelinase).

Tay-SaX (Tay-Sachs)

lacks heXosaminidase.

Hunters aim for the X

(X-linked recessive).

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

GM1

GM2

GM3

Lactosyl cerebroside

Glucocerebroside

Cerebroside

Tay-Sachs

Gaucher’s

Sulfatides

Galactocerebroside

Metachromatic

leukodystrophy

Globoside

Krabbe´s Sphingomyelin

Niemann-Pick

Fabry´s

Ceramide trihexoside

BIOCHEMISTRY-METABOLISM (continued)

Fatty acid

metabolism sites

Ketone bodies In liver: fatty acid and amino acids . acetoacetate + Breath smells like acetone

ß-hydroxybutyrate (to be used in muscle and brain). (fruity odor). Urine test for

Ketone bodies found in prolonged starvation and ketones does not detect

diabetic ketoacidosis. Excreted in urine. Made from ß-hydroxybutyrate (favored

HMG-CoA. Ketone bodies are metabolized by the by high redox state).

brain to 2 molecules of acetyl-CoA.

Cholesterol Rate-limiting step is catalyzed by HMG-CoA Lovastatin inhibits HMGsynthesis

reductase, which converts HMG-CoA to CoA reductase.

mevalonate. 2/3 of plasma cholesterol is esterified

by lecithin-cholesterol acyltransferase (LCAT).

100 BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

Fatty acid synthesis

Malonyl-CoA

Acetyl-CoA

Acetyl-CoA

Inner mitochondrial Citrate Carnitine

membrane shuttle shuttle

Mitochondrial matrix

Fatty acid + CoA

Acyl-CoA

Acyl-CoA

ß-oxidation

(breakdown to

acetyl-CoA groups)

Malonyl-CoA

Fatty acid degradation

occurs where its

products will be

consumed-in the

mitochondrion.

Cell cytoplasm

CO2 (biotin)

Fatty acid CoA

synthetase

Lipoproteins

Pancreatic lipase–degradation of dietary TG in small intestine.

Lipoprotein lipase–degradation of TG circulating in chylomicrons and VLDLs.

Hepatic TG lipase–degradation of TG remaining in IDL.

Hormone-sensitive lipase–degradation of TG stored in adipocytes.

Major A-I–Activates LCAT.

apolipoproteins B-100–Binds to LDL receptor.

C-II–Cofactor for lipoprotein lipase.

E–Mediates Extra (remnant) uptake.

Chylomicron

TG

CE

VLDL

Chylomicron

remnant

Lipoprotein

lipase

Lipoprotein

lipase

Modified

LDL

IDL E E

Atherosclerotic

plaque

TG = triglyceride, CE = cholesterol, FFA = free fatty acid

Small intestine

Hepatic

triglyceride

lipase

LDL

CE B-100

B-100 B-100

C-II

CE

B-100

E

Receptor

for B-100

Less

TG

CE

TG

B-48

C-II

A

E

TG

FFA

B-48

Eat TG

Pancreatic

lipase

FFA

Intestinal cells convert FFA back to TG

and package in chylomicrons

101

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

BIOCHEMISTRY-METABOLISM (continued)

Lipoprotein functions Lipoproteins are composed of varying proportions of cholesterol, triglycerides,

and phospholipids.

Function and route Apolipoproteins

Chylomicron Delivers dietary triglycerides to peripheral tissues and B-48 mediates secretion.

dietary cholesterol to liver. Secreted by intestinal A’s are used for formation of

epithelial cells. Excess causes pancreatitis, lipemia new HDL.

retinalis, and eruptive xanthomas. C-II activates lipoprotein lipase.

E mediates remnant uptake by

liver.

VLDL Delivers hepatic triglycerides to peripheral tissues. B-100 mediates secretion.

Secreted by liver. Excess causes pancreatitis. C-II activates lipoprotein lipase.

E mediates remnant uptake by

liver.

IDL Formed in the degradation of VLDL. Delivers

triglycerides and cholesterol to liver, where they

are degraded to LDL.

LDL Delivers hepatic cholesterol to peripheral tissues. B-100 mediates binding to cell

Formed by lipoprotein lipase modification of surface receptor for

VLDL in the peripheral tissue. Taken up by target endocytosis.

cells via receptor-mediated endocytosis. Excess

causes atherosclerosis, xanthomas, and arcus

corneae.

HDL Mediates centripetal transport of cholesterol (reverse A’s help form HDL structure.

cholesterol transport, from periphery to liver). Acts A-I in particular activates

as a repository for apoC and apoE (which are LCAT (which catalyzes

needed for chylomicron and VLDL metabolism). esterification of cholesterol).

Secreted from both liver and intestine. CETP mediates transfer of

cholesteryl esters to other

lipoprotein particles.

LDL and HDL carry most cholesterol. LDL HDL is Healthy.

transportscholesterol from liver to tissue; HDL LDL is Lousy.

transports it from periphery to liver.

Familial dyslipidemias

Elevated

Type Increased blood levels Pathophysiology

I–hyperchylomicronemia Chylomicrons TG, cholesterol Lipoprotein lipase deficiency

or altered apolipoprotein C-II

IIa–hypercholesterolemia LDL Cholesterol . LDL receptors

IIb–combined hyperlipidemia LDL, VLDL TG, cholesterol Hepatic overproduction of VLDL

III–dysbetalipoproteinemia IDL, VLDL TG, cholesterol Altered apolipoprotein E

IV–hypertriglyceridemia VLDL TG Hepatic overproduction of VLDL

V–mixed hypertriglyceridemia VLDL, chylomicrons TG, cholesterol . production/. clearance of

VLDL and chylomicrons

102 BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

103

Heme synthesis Underproduction of heme causes microcytic hypochromic anemia. Accumulation of

intermediates causes porphyrias.

Porphyrias

Lead poisoning Inhibits ferrochelatase and ALA dehydrase.

Coproporphyrin and ALA accumulate in urine.

Acute intermittent Deficiency in uroporphyrinogen I synthetase. Symptoms = 5 P’s: Painful

porphyria Porphobilinogen and d-ALA accumulate in urine. abdomen, Pink urine,

Porphyria cutanea Deficiency in uroporphyrinogen decarboxylase. Polyneuropathy,

tarda Uroporphyrin accumulates in urine (tea-colored). Psychological disturbances,

Photosensitivity. Precipitated by drugs.

Heme catabolism Heme is scavenged from RBCs and Fe2+ is reused. Heme .biliverdin .bilirubin (sparingly

water soluble, toxic to CNS, transported by albumin). Bilirubin is removed from blood by

liver, conjugated with glucuronate, and excreted in bile. In the intestine it is processed

into its excreted form. Some urobilinogen, an intestinal intermediate, is reabsorbed into

blood and excreted as urobilin into urine.

Hemoglobin Hemoglobin is composed of 4 polypeptide subunits Carbon monoxide has 200×

(2 a and 2 ß) and exists in 2 forms: greater affinity than O2

1. T (taut) form has low affinity for O2. for hemoglobin.

2. R (relaxed) form has high affinity for O2

(300×). Hemoglobin exhibits positive

cooperativity and negative allostery (accounts

for the sigmoid-shaped O2 dissociation curve

for hemoglobin), unlike myoglobin.

Hemoglobin structure . Cl-, H+, CO2, 2,3-BPG, and temperature favor When you’re Relaxed, you do

regulation T form over R form (shifts dissociation curve to your job better (carry O2).

right, leading to . O2 unloading). Fetal hemoglobin (2a and 2.

subunits) has lower affinity

for 2,3-BPG than adult

hemoglobin (HbA) and thus

has higher affinity for O2.

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

ß2 ß1

a2 a1

Heme

Succinyl CoA + Glycine

d-Aminolevolinic acid

(ALA)

Porphobilinogen

Pre-uroporphyrinogen

Committed step

ALA synthetase

Lead

poisoning

Heme

Protoporphyrin

Coproporphyrinogen

Uroporphyrinogen III

Porphyria

cutanea tarda

Fe2

Acute intermittent

porphyria

(-)

104

BIOCHEMISTRY-METABOLISM (continued)

Methemo- Iron in hemoglobin is in a reduced state (ferrous, Administer nitrites in cyanide

globinemia Fe2+). Methemoglobin is an oxidized form of poisoning to oxidize

hemoglobin (ferric, Fe3+) that does not bind O2 hemoglobin to

as readily but has . affinity for CN-. methemoglobin form.

Treat toxic levels of

METHemoglobin with

METHylene blue.

CO2 transport in CO2 binds to amino acids in globin chain (at N CO2 must be transported from

blood terminus) but not to heme. CO2 binding favors T tissue to lungs, the reverse

(taut) form of hemoglobin (and thus promotes O2 of O2 (occurs primarily in the

unloading). form of bicarbonate).

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

Specific IgG

in patient’s

blood

Peroxidase

enzyme

generates

color

Specific

antigen in

patient’s blood

Test antibody

1.

2.

Test

antigen

105

BIOCHEMISTRY-LABORATORY TECHNIQUES

Polymerase chain Molecular biology laboratory procedure that is used to synthesize many copies of a desired

reaction (PCR) fragment of DNA.

Steps:

1. DNA is denatured by heating to generate 2 separate strands

2. During cooling, excess premade DNA primers anneal to a specific sequence on each

strand to be amplified

3. Heat-stable DNA polymerase replicates the DNA sequence following each primer

These steps are repeated multiple times for DNA sequence amplification.

Molecular biology techniques

Southern blot A DNA sample is electrophoresed on a gel and then SNoW DRoP:

transferred to a filter. The filter is then soaked in a Southern = DNA

denaturant and subsequently exposed to a labeled Northern = RNA

DNA probe that recognizes and anneals to its Western = Protein

complementary strand. The resulting doublestranded

labeled piece of DNA is visualized

when the filter is exposed to film.

Northern blot Similar technique, except that Northern blotting

involves radioactive DNA probe binding to

sample RNA.

Western blot Sample protein is separated via gel electrophoresis

and transferred to a filter. Labeled antibody is

used to bind to relevant protein.

Enzyme-linked A rapid immunologic technique testing for ELISA is used in many

immunosorbent antigen-antibody reactivity. laboratories to determine

assay (ELISA) Patient’s blood sample is probed with either whether a particular

1. Test antigen (coupled to color-generating antibody (e.g., anti-HIV) is

enzyme)–to see if immune system present in a patient’s blood

recognizes it; or sample. Both the sensitivity

2. Test antibody (coupled to color-generating and the specificity of ELISA

enzyme)–to see if a certain antigen is approach 100%, but both

present false positive and false

If the target substance is present in the sample, negative results do occur.

the test solution will have an intense color

reaction, indicating a positive test result.

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

106

BIOCHEMISTRY-GENETICS

Genetic terms

Variable expression Nature and severity of the phenotype varies from 1 individual to another.

Incomplete Not all individuals with a mutant genotype show the mutant phenotype.

penetrance

Pleiotropy 1 gene has > 1 effect on an individual’s phenotype.

Imprinting Differences in phenotype depend on whether the mutation is of maternal or paternal

origin (e.g., AngelMan’s syndrome [Maternal], Prader-Willi syndrome [Paternal]).

Anticipation Severity of disease worsens or age of onset of disease is earlier in succeeding generations

(e.g., Huntington’s disease).

Loss of heterozygosity If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary

allele must be deleted/mutated before cancer develops. This is not true of oncogenes.

Dominant negative Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that

mutation also prevents the normal gene product from functioning.

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

disequilibrium expected by chance. Measured in a population, not in a family, and often varies in

different populations.

Mosaicism Occurs when cells in the body have different genetic makeup (e.g., lyonization–

random X inactivation in females).

Locus heterogeneity Mutations at different loci can produce the same phenotype (e.g., albinism).

Hardy-Weinberg If a population is in Hardy-Weinberg equilibrium, Hardy-Weinberg law assumes:

population then: 1.There is no mutation

genetics Disease prevalence: p2 + 2pq + q2 = 1 occurring at the locus

Allele prevalence: p + q = 1 2. There is no selection for

p and q are separate alleles; 2pq = heterozygote any of the genotypes at

prevalence. the locus

3. Mating is completely

random

4. There is no migration into or

out of the population

being considered

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

107

Modes of inheritance

Autosomal dominant Often due to defects in structural genes. Many Often pleiotropic and, in many

generations, both male and female, affected. cases, present clinically after

puberty. Family history

crucial to diagnosis.

Autosomal recessive 25% of offspring from 2 carrier parents are affected. Commonly more severe than

Often due to enzyme deficiencies. Usually seen in dominant disorders; patients

only 1 generation. often present in childhood.

X-linked recessive Sons of heterozygous mothers have a 50% chance of Commonly more severe in

being affected. No male-to-male transmission. males. Heterozygous females

may be affected.

X-linked dominant Transmitted through both parents. Either male or Hypophosphatemic rickets.

female offspring of the affected mother may

be affected, while all female offspring of the

affected father are diseased.

Mitochondrial Transmitted only through mother. All offspring of Leber’s hereditary optic

inheritance affected females may show signs of disease. neuropathy; mitochondrial

myopathies.

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

carrier

108

BIOCHEMISTRY-GENETICS (continued)

Autosomal-dominant diseases

Adult polycystic kidney Always bilateral, massive enlargement of kidneys due to multiple large cysts. Patients

disease present with pain, hematuria, hypertension, progressive renal failure. 90% of cases

are due to mutation in APKD1 (chromosome 16). Associated with polycystic liver

disease, berry aneurysms, mitral valve prolapse. Juvenile form is recessive.

Familial Elevated LDL owing to defective or absent LDL receptor. Heterozygotes (1:500) have

hypercholesterolemia cholesterol ˜ 300 mg/dL. Homozygotes (very rare) have cholesterol ˜ 700+ mg/dL,

(hyperlipidemia severe atherosclerotic disease early in life, and tendon xanthomas (classically in the

type IIA) Achilles tendon); MI may develop before age 20.

Marfan’s syndrome Fibrillin gene mutation . connective tissue disorders.

Skeletal abnormalities–tall with long extremities (arachnodactyly), hyperextensive

joints, and long, tapering fingers and toes (see Image 109).

Cardiovascular–cystic medial necrosis of aorta . aortic incompetence and

dissecting aortic aneurysms. Floppy mitral valve.

Ocular–subluxation of lenses.

Neurofibromatosis Findings: café-au-lait spots, neural tumors, Lisch nodules (pigmented iris

type 1 (von hamartomas). Also marked by skeletal disorders (e.g., scoliosis),

Recklinghausen’s pheochromocytoma, and . tumor susceptibility. On long arm of chromosome

disease) 17; 17 letters in von Recklinghausen.

Neurofibromatosis Bilateral acoustic neuroma, optic pathway gliomas, juvenile cataracts. NF2 gene on

type 2 chromosome 22; type 2 = 22.

Tuberous sclerosis Findings: facial lesions (adenoma sebaceum), hypopigmented “ash leaf spots” on skin,

cortical and retinal hamartomas, seizures, mental retardation, renal cysts, cardiac

rhabdomyomas. Incomplete penetrance, variable presentation.

Von Hippel-Lindau Findings: hemangioblastomas of retina/cerebellum/medulla; about half of affected

disease individuals develop multiple bilateral renal cell carcinomas and other tumors.

Associated with deletion of VHL gene (tumor suppressor) on chromosome 3 (3p).

Von Hippel-Lindau = 3 words for chromosome 3.

Huntington’s disease Findings: depression, progressive dementia, choreiform movements, caudate atrophy,

and . levels of GABA and ACh in the brain. Symptoms manifest in affected

individuals between the ages of 20 and 50. Gene located on chromosome 4; triplet

repeat disorder. “Hunting 4 food.”

Familial adenomatous Colon becomes covered with adenomatous polyps after puberty. Progresses to colon

polyposis cancer unless resected. Deletion on chromosome 5; 5 letters in “polyp.”

Hereditary Spheroid erythrocytes; hemolytic anemia; increased MCHC. Splenectomy is curative.

spherocytosis

Achondroplasia Autosomal-dominant cell-signaling defect of fibroblast growth factor (FGF) receptor 3.

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

Autosomal- Cystic fibrosis, albinism, a1-antitrypsin deficiency, phenylketonuria, thalassemias,

recessive sickle cell anemias, glycogen storage diseases, mucopolysaccharidoses (except Hunter’s),

diseases sphingolipidoses (except Fabry’s), infant polycystic kidney disease, hemochromatosis.

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

109

Cystic fibrosis Autosomal-recessive defect in CFTR gene on Infertility in males due to absent

chromosome 7. Defective Cl- channel .secretion vas deferens. Fat-soluble

of abnormally thick mucus that plugs lungs, vitamin deficiencies (A, D, E,

pancreas, and liver . recurrent pulmonary K). Can present as failure to

infections (Pseudomonas species and S. aureus), thrive in infancy.

chronic bronchitis, bronchiectasis, pancreatic Most common lethal genetic

insufficiency (malabsorption and steatorrhea), disease of Caucasians.

meconium ileus in newborns. . concentration Treatment: N-acetylcysteine

of Cl- ions in sweat test is diagnostic. to loosen mucous plugs.

X-linked recessive Fragile X, Duchenne’s muscular dystrophy, hemophilia A and B, Fabry’s, G6PD

disorders deficiency, Hunter’s syndrome, ocular albinism, Lesch-Nyhan syndrome, Bruton’s

agammaglobulinemia, Wiskott-Aldrich syndrome.

Female carriers of X-linked recessive disorders are rarely affected because of random

inactivation of X chromosomes in each cell.

Muscular dystrophies

Duchenne’s Frame-shift mutation . deletion of dystrophin Duchenne’s = Deleted

(X-linked) gene . accelerated muscle breakdown. Onset Dystrophin.

before 5 years of age. Weakness begins in pelvic Diagnose muscular dystrophies

girdle muscles and progresses superiorly. by . CPK and muscle

Pseudohypertrophy of calf muscles due to biopsy.

fibrofatty replacement of muscle; cardiac myopathy.

The use of Gowers’ maneuver, requiring assistance

of the upper extremities to stand up, is characteristic

(indicates proximal lower limb weakness).

Becker’s Mutated dystrophin gene is less severe than

Duchenne’s.

Fragile X syndrome X-linked defect affecting the methylation and Triplet repeat disorder (CGG)n

expression of the FMR1 gene. The 2nd most that may show genetic

common cause of genetic mental retardation anticipation (germlike

(the most common cause is Down syndrome). expansion in females).

Associated with macro-orchidism (enlarged testes), Fragile X = eXtra-large

long face with a large jaw, large everted ears, testes, jaw, ears.

and autism.

Trinucleotide repeat Huntington’s disease, myotonic dystrophy, Try (trinucleotide) hunting

expansion diseases Friedreich’s ataxia, fragile X syndrome. May show for my fried eggs (X).

anticipation (disease severity . and age of onset

. in successive generations).

Common congenital 1. Heart defects

malformations 2. Hypospadias

3. Cleft lip (with or without cleft palate)

4. Congenital hip dislocation

5. Spina bifida

6. Anencephaly

7. Pyloric stenosis Associated with projectile

vomiting.

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

110

BIOCHEMISTRY-GENETICS (continued)

Autosomal trisomies

Down syndrome Most common chromosomal disorder and cause of Drinking age (21).

(trisomy 21), 1:700 congenital mental retardation. Findings: mental . levels of a-fetoprotein,

retardation, flat facial profile, prominent epicanthal . ß-hCG, . nuchal

folds, simian crease, duodenal atresia, congenital translucency.

heart disease (most common malformation is

septum primum-type ASD due to endocardial

cushion defects), Alzheimer’s disease in affected

individuals > 35 years old, . risk of ALL.

95% of cases due to meiotic nondisjunction of homologous

chromosomes; associated with advanced maternal

age (from 1:1500 in women < 20 to 1:25 in

women > 45). 4% of cases due to robertsonian

translocation, and 1% of cases due to Down

mosaicism (no maternal association) (see

Image 110).

Edwards’ syndrome Findings: severe mental retardation, rocker bottom Election age (18).

(trisomy 18), feet, low-set ears, micrognathia (small jaw),

1:8000 congenital heart disease, clenched hands,

prominent occiput. Death usually occurs within

1 year of birth.

Patau’s syndrome Findings: severe mental retardation, microphthalmia, Puberty (13).

(trisomy 13), microcephaly, cleft lip/palate, abnormal forebrain

1:6000 structures, polydactyly, congenital heart disease.

Death usually occurs within 1 year of birth.

Cri-du-chat Congenital deletion of short arm of chromosome 5 Cri du chat = cry of the cat.

syndrome (46,XX or XY, 5p-).

Findings: microcephaly, severe mental retardation,

high-pitched crying/mewing, epicanthal folds,

cardiac abnormalities.

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

NONDISJUNCTION

n – 1 n – 1

Anaphase I

Anaphase II

n + 1 n + 1 n – 1 n + 1 n n

111

22q11 syndromes Cleft palate, Abnormal facies, Thymic aplasia . CATCH-22.

T-cell deficiency, Cardiac defects, Hypocalcemia

2° to parathyroid aplasia, microdeletion at

chromosome 22q11. Variable presentation as

DiGeorge syndrome (thymic, parathyroid, and

cardiac defects) or velocardiofacial syndrome

(palate, facial, and cardiac defects).

Fetal alcohol Newborns of mothers who consumed significant amounts of alcohol (teratogen) during

syndrome pregnancy (highest risk at 3-8 weeks) have . incidence of congenital abnormalities,

including pre- and postnatal developmental retardation, microcephaly, facial

abnormalities, limb dislocation, and heart and lung fistulas. Mechanism may include

inhibition of cell migration. The number one cause of congenital malformations in

the United States.

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

112

BIOCHEMISTRY-NUTRITION

Vitamins

Vitamins: fat A, D, E, K. Absorption dependent on gut (ileum) Malabsorption syndromes

soluble and pancreas. Toxicity more common than (steatorrhea), such as cystic

for water-soluble vitamins, because these fibrosis and sprue, or mineral

accumulate in fat. oil intake can cause fatsoluble

vitamin deficiencies.

Vitamins: water B1 (thiamine: TPP) All wash out easily from body

soluble B2 (riboflavin: FAD, FMN) except B12 (stored in liver).

B3 (niacin: NAD+) B-complex deficiencies often

B5 (pantothenate: CoA) result in dermatitis,

B6 (pyridoxine: PP) glossitis, and diarrhea.

B12 (cobalamin)

C (ascorbic acid)

Biotin

Folate

Vitamin A (retinol)

Deficiency Night blindness, dry skin, and impaired immune Retinol is vitamin A, so think

response. Retin-A (used topically for

Function Constituent of visual pigments (retinal). wrinkles and acne).

Excess Arthralgias, fatigue, headaches, skin changes, sore

throat, alopecia.

Vitamin B1 (thiamine)

Deficiency Beriberi and Wernicke-Korsakoff syndrome. Seen Spell beriberi as Ber1Ber1.

in alcoholism and malnutrition. Dry beriberi–polyneuritis,

Function In thiamine pyrophosphate, a cofactor for oxidative muscle wasting.

decarboxylation of a-keto acids (pyruvate, Wet beriberi–high-output

a-ketoglutarate) and a cofactor for cardiac failure (dilated

transketolase in the HMP shunt. cardiomyopathy), edema.

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

Vitamins

Water soluble

Vitamin A-Vision

Vitamin D-Bone calcification

-Ca2+ homeostasis

Vitamin K-Clotting factors

Vitamin E-Antioxidant

Fat soluble

Metabolic

-Thiamine–B1

-Riboflavin–B2 12

-Niacin–B3

-Biotin

-Pantothenic acid

Vitamin C

Folate–Blood,

neural development

Cobalamin–B -blood,

CNS

Pyridoxine–B

Pyridoxal–B

Pyridoxamine–B

6

6

6

113

Vitamin B2 (riboflavin)

Deficiency Angular stomatitis, Cheilosis, Corneal The 2 C’s.

vascularization. FAD and FMN are derived from

Function Cofactor in oxidation and reduction (e.g., FADH2). riboFlavin (B2 = 2 ATP).

Vitamin B3 (niacin)

Deficiency Pellagra can be caused by Hartnup disease Pellagra’s symptoms are the 3

(. tryptophan absorption), malignant D’s: Diarrhea, Dermatitis,

carcinoid syndrome (. tryptophan Dementia (also beefy

metabolism), and INH (. vitamin B6). glossitis).

Function Constituent of NAD+, NADP+ (used in redox NAD derived from Niacin

reactions). Derived from tryptophan (B3 = 3 ATP).

using vitamin B6.

Vitamin B5 (pantothenate)

Deficiency Dermatitis, enteritis, alopecia, adrenal insufficiency.

Function Constituent of CoA (a cofactor for acyl transfers) Pantothen-A is in Co-A.

and component of fatty acid synthase.

Vitamin B6 (pyridoxine)

Deficiency Convulsions, hyperirritability (deficiency inducible by INH and oral contraceptives),

peripheral neuropathy.

Function Converted to pyridoxal phosphate, a cofactor used in transamination (e.g., ALT and AST),

decarboxylation, and heme synthesis.

Vitamin B12 (cobalamin)

Deficiency Macrocytic, megaloblastic anemia; neurologic Found only in animal products.

symptoms (optic neuropathy, subacute combined Vitamin B12 deficiency is

degeneration, paresthesia); glossitis. usually caused by

Function Cofactor for homocysteine methylation malabsorption (sprue,

(transfers CH3 groups as methylcobalamin) enteritis, Diphyllobothrium

and methylmalonyl-CoA handling. latum), lack of intrinsic factor

Stored primarily in the liver. (pernicious anemia), or

Synthesized only by microorganisms. absence of terminal ileum

(Crohn’s disease).

Use Schilling test to detect

deficiency.

Abnormal myelin is seen in B12

Homocysteine + N-methyl THF

B12

Methionine + THF deficiency, possibly due to

Methylmalonyl-CoA

B12

Succinyl-CoA

. methionine or .

methylmalonic acid (from

metabolism of accumulated

methylmalonyl-CoA).

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

114

BIOCHEMISTRY-NUTRITION (continued)

Folic acid

Deficiency Most common vitamin deficiency in the United FOLate from FOLiage.

States. Eat green leaves (because folic

Macrocytic, megaloblastic anemia (often no acid is not stored very long).

neurologic symptoms, as opposed to vitamin Supplemental folic acid in

B12 deficiency). early pregnancy reduces

Function Coenzyme (tetrahydrofolate) for 1-carbon neural tube defects.

transfer; involved in methylation reactions. PABA is the folic acid

Important for the synthesis of nitrogenous bases precursor in bacteria. Sulfa

in DNA and RNA. drugs and dapsone

(antimicrobials) are PABA

analogs.

Biotin

Deficiency Dermatitis, enteritis. Caused by antibiotic use, “AVIDin in egg whites

ingestion of raw eggs. AVIDly binds biotin.”

Function Cofactor for carboxylations:

1. Pyruvate . oxaloacetate

2. Acetyl-CoA . malonyl-CoA

3. Proprionyl-CoA . methylmalonyl-CoA

Vitamin C (ascorbic acid)

Deficiency Scurvy–swollen gums, bruising, anemia, poor Vitamin C Cross-links

Function wound healing. Collagen. British sailors

Necessary for hydroxylation of proline and lysine in carried limes to prevent

collagen synthesis. scurvy (origin of the word

Facilitates iron absorption by keeping iron in Fe+2 “limey”).

reduced state (more absorbable)

Necessary as a cofactor for dopamine .NE.

Vitamin D D2 = ergocalciferol, consumed in milk. Remember that drinking milk

D3 = cholecalciferol, formed in sun-exposed skin. (fortified with vitamin D) is

25-OH D3 = storage form. good for bones.

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

Deficiency Rickets in children (bending bones), osteomalacia

in adults (soft bones), and hypocalcemic tetany.

Function . intestinal absorption of calcium and phosphate.

Excess Hypercalcemia, loss of appetite, stupor. Seen in

sarcoidosis, a disease where the epithelioid

macrophages convert vitamin D into its active form.

Vitamin E

Deficiency Increased fragility of erythrocytes. Vitamin E is for Erythrocytes.

Function Antioxidant (protects erythrocytes from hemolysis).

BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

115

Vitamin K

Deficiency Neonatal hemorrhage with . PT and . aPTT but K for Koagulation. Note that

normal bleeding time. the vitamin K-dependent

Function Catalyzes .-carboxylation of glutamic acid residues clotting factors are II, VII,

on various proteins concerned with blood clotting. IX, X, and protein C and S.

Synthesized by intestinal flora. Therefore, vitamin Warfarin is a vitamin K

K deficiency can occur after the prolonged use of antagonist.

broad-spectrum antibiotics.

Zinc deficiency Delayed wound healing, hypogonadism, . adult hair (axillary, facial, pubic); may

predispose to alcoholic cirrhosis.

Ethanol metabolism Disulfiram (Antabuse) inhibits

acetaldehyde dehydrogenase

(acetaldehyde accumulates,

contributing to hangover

symptoms).

NAD+ is the limiting reagent.

Alcohol dehydrogenase operates via zero-order

` kinetics.

Ethanol Ethanol metabolism . NADH/NAD+ ratio in liver, causing diversion of pyruvate

hypoglycemia to lactate and OAA to malate, thereby inhibiting gluconeogenesis and leading to

hypoglycemia. This altered NADH/NAD+ ratio is responsible for the hepatic fatty

change (hepatocellular steatosis) seen in chronic alcoholics (shunting away from

glycolysis and toward fatty acid synthesis).

Kwashiorkor vs. Kwashiorkor–protein malnutrition resulting in skin Kwashiorkor results from a

marasmus lesions, edema, liver malfunction (fatty change). protein-deficient MEAL:

Clinical picture is small child with swollen belly. Malabsorption

Marasmus–protein-calorie malnutrition resulting in Edema

tissue wasting. Anemia

Liver (fatty)

HIGH-YI E LD PRINCIPLES BIOCHEMISTRY

Ethanol

Alcohol

dehydrogenase

Acetaldehyde

Acetaldehyde

dehydrogenase

Acetate

NAD+ NADH NAD+ NADH

1. Pyruvate lactate

NADH NAD+

2. Oxaloacetate malate

NADH NAD+

116 BIOCHEMISTRY HIGH-YI E LD PRINCIPLES

NOTES

H I G H -Y I E L D P R I N C I P L E S I N

Embryology

117

“Zygote. This cell, formed by the union of an ovum and a sperm, represents the

beginning of a human being.”

–Keith Moore and Vid Persaud,

Before We Are Born

Embryology is traditionally one of the higher-yield areas within

anatomy. This topic can be crammed closer to the exam date. Many

questions focus on underlying mechanisms of congenital malformations

(e.g., failure of fusion of the maxillary and medial nasal

processes leading to cleft palate).

118

Fetal landmarks

Day 0 Fertilization by sperm,

initiating embryogenesis.

Within week 1 Implantation (as a blastocyst).

Within week 2 Bilaminar disk.

Within week 3 Gastrulation.

Primitive streak,

notochord,

and neural plate begin to form.

Weeks 3-8 Neural tube formed.

Organogenesis.

Extremely susceptible to teratogens.

Week 4 Heart begins to beat.

Upper and lower limb buds begin to form.

Week 10 Genitalia have male/female characteristics.

Early development

Rule of 2’s for 2nd 2 germ layers (bilaminar disk): epiblast, hypoblast. The epiblast (precursor to

week 2 cavities: amniotic cavity, yolk sac. ectoderm) invaginates to

2 components to placenta: cytotrophoblast, form primitive streak. Cells

syncytiotrophoblast. from the primitive streak give

Rule of 3’s for 3rd 3 germ layers (gastrula): ectoderm, mesoderm, rise to both intraembryonic

week endoderm. mesoderm and endoderm.

Embryologic derivatives

Ectoderm

Surface ectoderm Adenohypophysis, lens of eye, epithelial linings, epidermis.

Neuroectoderm Neurohypophysis, CNS neurons, oligodendrocytes, astrocytes, ependymal cells, pineal gland.

Neural crest ANS, dorsal root ganglia, cranial nerves, melanocytes, chromaffin cells of adrenal medulla,

enterochromaffin cells, pia and arachnoid, celiac ganglion, Schwann cells, odontoblasts,

parafollicular (C) cells of thyroid, laryngeal cartilage, bones of the skull.

Mesoderm Dura mater, connective tissue, muscle, bone, cardiovascular structures, lymphatics, blood,

urogenital structures, serous linings of body cavities (e.g., peritoneal), spleen,

adrenal cortex, kidneys.

Endoderm Gut tube epithelium and derivatives (e.g., lungs, liver, pancreas, thymus, parathyroid, thyroid

follicular cells).

Notochord Induces ectoderm to form neuroectoderm (neural plate). Its postnatal derivative is the

nucleus pulposus of the intervertebral disk.

EMBRYOLOGY HIGH-YI E LD PRINCIPLES

Day 2

Zygote

Day 3

Day 5

Blastocyst

Day 6

Implantation

Day 18

Day 21

Day 0

Fertilization

Morula

Endometrium

Neural plate

Neural crest

Neural

crest

cells

Neural tube

Uterine

wall

Notochord

119

Teratogens Most susceptible in 3rd-8th weeks (organogenesis) of pregnancy.

Examples Effects on fetus

Alcohol Birth defects and mental

retardation (leading cause);

fetal alcohol syndrome

ACE inhibitors Renal damage

Cocaine Abnormal fetal development

and fetal addiction

Diethylstilbestrol (DES) Vaginal clear cell

adenocarcinoma

Iodide Congenital goiter or

hypothyroidism

13-cis-retinoic acid Extremely high risk for birth

defects

Thalidomide Limb defects (“flipper” limbs)

Tobacco Preterm labor, placental

problems, attention-deficit

hyperactivity disorder

(ADHD)

Warfarin, x-rays Multiple anomalies

Fetal infections can also cause congenital malformations. (Other medications

contraindicated in pregnancy are shown in the pharmacology section.)

Twinning

HIGH-YI E LD PRINCIPLES EMBRYOLOGY

Monozygotic

1 zygote splits evenly to develop 2 amniotic

sacs with a single common chorion and placenta.

1 chorion

2 amniotic

sacs

1 placenta

Dizygotes develop individual placentas, chorions,

and amniotic sacs.

Monozygotes develop 2 placentas (separate/fused),

chorions, and amniotic sacs.

Dizygotic (fraternal) or monozygotic

2 placentas

2 amniotic sacs

2 chorions

120

Umbilical cord Contains 2 umbilical arteries, which return Single umbilical artery is

deoxygenated blood from fetal internal associated with congenital

iliac arteries, and 1 umbilical vein, which and chromosomal

supplies oxygenated blood from the placenta anomalies.

to the fetus.

Allantoic duct removes nitrogenous waste (from

fetal bladder, like a urethra).

Heart embryology

Embryonic structure Gives rise to

Truncus arteriosus Ascending aorta and pulmonary

trunk

Bulbus cordis Smooth parts of left and right

ventricle

Primitive ventricle Trabeculated parts of left and

right ventricle

Primitive atria Trabeculated left and

right atrium

Left horn of sinus venosus (SV) Coronary sinus

Right horn of SV Smooth part of right atrium

Right common cardinal vein and right anterior SVC

cardinal vein

Fetal erythropoiesis Fetal erythropoiesis occurs in: Young Liver Synthesizes Blood.

1. Yolk sac (3-8 wk) Fetal hemoglobin = a2.2.

2. Liver (6-30 wk) Adult hemoglobin = a2ß2.

3. Spleen (9-28 wk)

4. Bone marrow (28 wk onward)

EMBRYOLOGY HIGH-YI E LD PRINCIPLES

Umbilical artery

Allantoic duct

Amniotic epithelium

Umbilical artery

Umbilical vein

Wharton´s jelly

121

Fetal circulation Blood in umbilical vein is ˜ 80%

saturated with O2.

3 important shunts:

1. Most oxygenated blood

reaching the heart via the

IVC is diverted through

the foramen ovale and

pumped out the aorta to

the head.

2. Deoxygenated blood from

the SVC is expelled into

the pulmonary artery and

ductus arteriosus to the

lower body of the fetus.

3. Blood entering the fetus

through the umbilical vein

is conducted via the

ductus venosus into the

IVC.

At birth, infant takes a breath;

. resistance in pulmonary

vasculature causes . left atrial

pressure vs. right atrial

pressure; foramen ovale

closes; . in O2 leads to

. in prostaglandins, causing

closure of ductus arteriosus.

Indomethacin closes the PDA.

Prostaglandins keep a patent

PDA open.

Fetal-postnatal 1. Umbilical vein–ligamentum teres hepatis The urachus is the part of the

derivatives 2. UmbiLical arteries–mediaL umbilical ligaments allantoic duct between the

3. Ductus arteriosus–ligamentum arteriosum bladder and the umbilicus.

4. Ductus venosus–ligamentum venosum Urachal cyst or sinus is a

5. Foramen ovale–fossa ovalis remnant.

6. AllaNtois–urachus–mediaN umbilical ligament

7. Notochord–nucleus pulposus of intervertebral disk

Aortic arch 1st–part of MAXillary artery. 1st arch is MAXimal.

derivatives 2nd–Stapedial artery and hyoid artery. Second = Stapedial.

3rd–common Carotid artery and proximal part of C is 3rd letter of alphabet.

internal carotid artery.

4th–on left, aortic arch; on right, proximal part of 4th arch (4 limbs) = systemic.

right subclavian artery.

6th–proximal part of pulmonary arteries and (on 6th arch = pulmonary and the

left only) ductus arteriosus. pulmonary-to-systemic shunt

(ductus arteriosus).

HIGH-YI E LD PRINCIPLES EMBRYOLOGY

(Adapted, with permission, from Ganong WF. Review of Medical Physiology, 19th ed. Stamford, CT:

Appleton & Lange, 1999:600.)

4th 4th

3rd 3rd

6th 6th

122

Branchial Composed of branchial clefts, arches, and pouches. CAP covers outside from inside

apparatus Branchial clefts are derived from ectoderm. (Clefts = ectoderm, Arches =

Branchial arches are derived from mesoderm and mesoderm, Pouches =

neural crests. endoderm).

Branchial pouches are derived from endoderm. Branchial apparatus is also

called pharyngeal apparatus.

Clefts are also called grooves.

Branchial arch 1 Meckel’s cartilage: Mandible, Malleus, incus, sphenoMandibular ligament.

derivatives Muscles: Muscles of Mastication (temporalis, Masseter, lateral and Medial pterygoids),

Mylohyoid, anterior belly of digastric, tensor tympani, tensor veli palatini, anterior

2/3 of tongue.

Nerve: CN V2 and CN V3.

Branchial arch 2 Reichert’s cartilage: Stapes, Styloid process, lesser horn of hyoid, Stylohyoid ligament.

derivatives Muscles: muscles of facial expression, Stapedius, Stylohyoid, posterior belly of digastric.

Nerve: CN VII.

Branchial arch 3 Cartilage: greater horn of hyoid. Think of pharynx:

derivatives Muscle: stylopharyngeus. stylopharyngeus innervated

Nerve: CN IX. by glossopharyngeal nerve.

Branchial arches Cartilages: thyroid, cricoid, arytenoids, corniculate, Arches 3 and 4 form posterior

4-6 derivatives cuneiform. 1/3 of tongue.

Muscles (4th arch): most pharyngeal constrictors, Arch 5 makes no major

cricothyroid, levator veli palatini. developmental

Muscles (6th arch): all intrinsic muscles of larynx contributions.

except cricothyroid.

Nerve: 4th arch–CN X (superior laryngeal branch);

6th arch–CN X (recurrent laryngeal branch).

Branchial arch Arch 1 derivatives supplied by CN V2

innervation and V3.

Arch 2 derivatives supplied by CN VII.

Arch 3 derivatives supplied by CN IX.

Arch 4 and 6 derivatives supplied

by CN X.

EMBRYOLOGY HIGH-YI E LD PRINCIPLES

Primitive esophagus

Pharyngeal

arches

CN V

CN VII

CN IX

CN X

Epicardial ridge

1st

2nd

3rd

4th

Primitive pharynx

123

Tongue 1st branchial arch forms anterior 2/3 (thus sensation Taste is CN VII, IX, X

development via CN V3, taste via CN VII). (solitary nucleus);

3rd and 4th arches form posterior 1/3 (thus sensation pain is CN V3, IX, X;

and taste mainly via CN IX, extreme posterior motor is CN XII.

via CN X).

Motor innervation is via CN XII.

Branchial cleft 1st cleft develops into external auditory meatus. Persistent cervical sinus can

derivatives 2nd through 4th clefts form temporary cervical sinuses, lead to a branchial cyst in the

which are obliterated by proliferation of 2nd arch neck.

mesenchyme.

Ear development

Bones Muscles Miscellaneous

Malleus/incus– Tensor tyMpani (V3)–1st arch External auditory meatus–

1st arch 1st cleft

Stapes–2nd arch Stapedius (VII)–2nd arch

Eardrum, eustachian tube–1st

branchial membrane

(branchial membranes are

located at junctions of clefts

with pouches)

Branchial pouch 1st pouch develops into middle ear cavity, eustachian 1st pouch contributes to

derivatives tube, mastoid air cells. endoderm-lined structures

2nd pouch develops into epithelial lining of palatine of ear.

tonsil. 3rd pouch contributes to 3

3rd pouch (dorsal wings) develops into inferior structures (thymus, left and

parathyroids. right inferior parathyroids).

3rd pouch (ventral wings) develops into thymus. Aberrant development of 3rd

4th pouch develops into superior parathyroids. and 4th pouches .

DiGeorge syndrome .

leads to T-cell deficiency

(thymic aplasia) and

hypocalcemia (failure of

parathyroid development).

HIGH-YI E LD PRINCIPLES EMBRYOLOGY

Taste/sensation via

IX

X

X X

Taste via VII

Arches 3, 4

Arch 1

Sensation via

V3

124

Thyroid Thyroid diverticulum arises from floor of primitive

development pharynx, descends into neck. Connected to tongue by

thyroglossal duct, which normally disappears but may

persist as pyramidal lobe of thyroid. Foramen cecum

is normal remnant of thyroglossal duct. Most

common ectopic thyroid tissue site is the tongue.

Cleft lip and cleft Cleft lip–failure of fusion of the maxillary and medial

palate nasal processes (formation of 1° palate).

Cleft palate–failure of fusion of the lateral palatine

processes, the nasal septum, and/or the median

palatine process (formation of 2° palate).

Diaphragm Diaphragm is derived from: Several Parts Build Diaphragm.

embryology 1. Septum transversum Diaphragm descends during

2. Pleuroperitoneal folds development but maintains

3. Body wall innervation from above

4. Dorsal mesentery of esophagus C3-C5. “C3, 4, 5 keeps the

diaphragm alive.”

Abdominal contents may

herniate into the thorax due

to incomplete development

(hiatal hernia).

Pancreas Pancreas is derived from the foregut. Ventral pancreatic bud becomes pancreatic head,

and spleen uncinate process (lower half of head), and main pancreatic duct. Dorsal pancreatic

embryology bud becomes everything else (body, tail, isthmus, and accessory pancreatic duct).

Spleen arises from dorsal mesentery but is supplied by artery of foregut.

Annular pancreas–ventral and dorsal pancreatic buds abnormally encircle duodenum;

forms a ring of pancreatic tissue that may cause duodenal narrowing.

EMBRYOLOGY HIGH-YI E LD PRINCIPLES

Persistent

thyroglossal

duct

Thyroid

gland

Trachea

Thymus

Foramen cecum

Cleft lip

Cleft palate (partial)

Roof of

mouth

Nasal

cavity

Aorta

Pleuroperitoneal

folds

Dorsal

esophageal

mesoderm Inferior vena cava

Foregut

Septum transversum

Body wall

Pancreatic

duct

Main

pancreatic duct

Ventral

pancreatic

bud Dorsal

pancreatic

bud

Gallbladder

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