First Aid Biochem

Biochemistry section of First Aid 2012
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Histone octamers consist primarily of which two amino acids?
Lysine and Arginine (both positively charged)
What histones are nucleosome beads composed of?
H2A, H2B, H3, H4 (two sets each, form an octamer)
What is the function of histone H1?
H1 ties nucleosome beads together in a string.
Which histone is not a part of the nucleosome core?
H1
What is heterochromatin?
DNA that is condensed, transcriptionally inactive, and sterically inaccessible.
What is euchromatin?
DNA that is less condensed, is transcriptionally active, and is sterically accessible.
What occurs to make heterochromatin into euchromatin?
Acetylation of the histone structure causes the DNA to loosen around the nucleosome core.
(Acetylation = Activates)
Which are the purines?
Adenine and Guanine (both have two rings)
Which are the pyrimidines?
Cytosine, Uracil, and Thymine (all have one ring)
How is uracil made?
Deamination of cytosine
What is the group attached to thymine?
a methyl group
Which nucleotide bonds are the strongest, resulting in higher melting temperatures when abundant?
A-G (have three H-bonds)
Which nucleotide bonds have only two H-bonds?
A-T (creates lower melting temperatures)
What special group is found on purines?
N(10)-formyl-tetrafolate
(two groups per purine)
Which amino acids are necessary for purine synthesis?
Glycine, Aspartate, Glutamine
What is a nucleoside composed of?
base + ribose
What is a nucleotide composed of?
base + ribose + phosphate linked with 5'-3' phosphodiesterase bond
What is the purine precursor?
IMP (inosine monophosphate)
What is the pyrimidine precursor?
Orotate (with PRPP, phosphoribosyl pyrophosphate, added later)
Ribonucleotides are converted to deoxyribonucleotides by?
Ribonucleotide reductase
Which two pathways involve carbamoyl phosphate?
1. De novo pyrimidine synthesis (CPS II)
2. Urea cycle (CPS I)
Ornithine transcarbamoylase deficiency (OTC Deficiency) in the urea cycle causes what?
1. Accumulation of carbamoyl phosphate
- Converted to orotic acid --> orotic acidemia.
Orotic acidemia can be caused by defects in which two enzymes?
1. Orotic acid phosphoribosyltransferase
2. Orotidine 5'-phosphate decarboxylase
What is the genetic inheritance of orotic acidemia?
autosomal recessive
Both of the enzyme defects possible in orotic acidemia ultimately cause?
Lack of ability to convert Orotic Acid to UMP
What are the findings in orotic aciduria?
1. Increased urine orotic acid
2. Folate independent megaloblastic anemia
3. Failure to thrive
4. Normal Ammonemia
How do you treat orotic aciduria?
Oral Uridine
(works via the pyrimidine salvage pathway)
What does adenosine deaminase deficiency cause?
Decreased lymphocyte count
- Due to decreased DNA synthesis
- Excess ATP and dATP inhibit ribonucleotide reductase
- Results in SCID
Adenosine deaminase deficiency is one of the major causes of which disease?
SCID severe combined immunodeficiency disease
What was the first disease to be treated by gene therapy?
SCID
- Adenosine Deaminase
What is the defect in Lesch-Nyhan syndrome?
Absence of HGPRT
(hypoxanthine guanine phosphoribosyltransferase)
What is the function of HGPRT?
converts hypoxanthine to IMP
converts guanine to GMP
What happens in Lesch-Nyhan syndrome?
Can't salvage purines: excess uric acid production.
What is the clinical presentation of Lesch-Nyhan syndrome?
Retardation
Self-mutilation
Aggression
Hyperuricemia / Gout
Choreoathetosis
Urate Nephropathy
What is the mode of transmission of Lesch-Nyhan syndrome?
X-linked recessive
What is the precursor for purines?
IMP (inosine monophosphate)
What is the precursor for pyrimidines?
Orotate (with PRPP added later)
In DNA replication, what is a transition?
Substituting a purine-purine, or pyrimidine-pyrimidine
transItion is Identical
In DNA replication, what is a transversion?
Substituting a purine for a pyrimidine, or vice versa.
"transVersion = conVersion of type"
In relation to genetic code, what does degenerate mean?
Multiple codons may code for the same amino acid
In relation to genetic code, what does commaless mean?
Read from a fixed start point as continuous sequence of bases
In genetic code, what does universal mean?
Genetic code is conserved throughout evolution.
What are exceptions to universal code?
Mitochondria, archaebacteria, Mycoplasma, and some yeasts
What are exceptions to commaless code?
Some viruses
What is a non-degenerate code?
Methionine is only coded for by AUG (start)
What is a silent DNA mutation?
Same amino acid, change at 3rd position due to tRNA wobble
What is a missense mutation?
The amino acid has been changed, but is similar in chemical structure
What is a nonsense mutation?
Change resulting in an early STOP codon
"stop the nonsense!"
What is a frame shift mutation?
Change resulting in misreading of downstream codons. Results in truncated, non-functional protein.
What is the origin of replication?
Genomic sequence were replication begins
- Single in prokaryotes
- Multiple in eukaryotes
What is the role of helicase?
It unwinds DNA at the replication fork.
What prevents DNA from reannealing during replication?
Single-stranded binding proteins
What is the role of DNA topoisomerases?
They create a nick in the helix to relieve supercoil during replication.
What is the role of primase?
It makes an RNA primer on which DNA polymerase III can initiate replication (in prokaryotes)
What is the role of DNA polymerase III?
(prokaryotes)
1. It elongate the leading strand by adding deoxynucleotides to the 3' end.
2. Elongates lagging strand too.
3. 3' --> 5' exonuclease proofreading activity
What is the MOA of flouroquinolones?
They inhibit DNA gyrase (specific prokaryotic topoisomerase)
What is the role of DNA polymerase I?
(prokaryote) Degrades the RNA primer with 5' --> 3' exonuclease activity and fills gap with DNA.
What is the role of DNA ligase?
Seals
What is nucleotide repair?
1. Endonucleases release oligonucleotides containing damaged bases
2. DNA polymerase fills
3. Ligase reseals the gap
What is base excision repair?
1. Glycosylases recognize/remove damaged bases
2. AP endonucleases cut DNA at apyrimidic site
3. Empty sugar removed, gap is filled/sealed.
What is mismatch repair?
Unmethylated new string has mismatched nucleotides removed
- Gap is filled/sealed.
What is the defect in Xeroderma Pigmentosum?
Xeroderma pigmentosum: mutated nucleotide excision repair --> prevents repair of thymidine dimers.
What is the defect in HNPCC?
Mutated mismatch repair (APC gene)
On incoming DNA, where is the triphosphate?
On the 5' end
Which is the most abundant RNA?
rRNA
"rampant"
What is the longest type of RNA?
mRNA
"massive"
What is the smallest type of RNA?
tRNA
"tiny"
What is the prokaryotic start codon coding for?
formyl-methionine (f-met)
What are the mRNA stop codons?
UGA you go away
UAA you are away
UAG you are gone
List the organization of a gene:
5'
- promoter - enhancer - promoter
- tata
- initiation site
- coding region of exons/introns
- aataa tail
3'
Where does RNA polymerase (or other transcription factors) bind DNA?
Promoter Site
What is the result of promoter site mutations?
dramatic decrease in amount of that gene transcribed
RNA polymerase I makes?
rRNA in eukaryotes
RNA polymerase II makes?
mRNA in eukaryotes
It opens DNA at promoter site
RNA polymerase III makes?
tRNA in eukaryotes?
What is the order of RNA as it is used?
RNA pol 1 = rRNA
RNA pol 2= mRNA
RNA pol 3 = tRNA

Ribosome -> Messenger -> Transfer
Why does alpha-amanitin cause liver failure?
It inhibits RNA polymerase II (mRNA)
(found in death cap mushrooms)
What are the steps in RNA processing?
Occurs in Nucleus
- 5' cap of 7-methylguanosine
- 3' tail polyadenylation ~200 A
- Splicing out of introns
What is hnRNA?
Unprocessed nuclear RNA
What is mRNA
Processed (capped/tailed) RNA
What is the polyadenylation signal, and how is it transcribed.
AAUAAA
- transcribed by poly-a-polymerase w/o template
How does pre-mRNA splicing occur?
(1) Transcript combines with snRNPs, et to form spliceosome
(2) Lariat intermediate generated
(3) Lariate releases introns, joins together exons.
What is the defect in lupus (regarding RNA)?
Antibodies to spliceosomal snRNPs
An example of alternative splicing mutations in seen in?
beta-thalassemia mutations
Describe tRNA structure:
Secondary structure is a cloverleaf
Anticodon end is opposite 3' aminoacyl end
Amino Acid binds 3' End
What sequence is at every 3' end of tRNA?
CCA
What is responsible for the accuracy of amino acid selection in tRNA formation?
Aminoacyl-tRNA synthetase and binding of charged tRNA
What is the MOA of tetracylines?
Bind the 30S subunit (prevent attachment of aminoacyl-tRNA)
What is the function of aminoacyl-tRNA synthetase?
Charges tRNA for appropriate amino acid binding
- Inhibited by Aminoglycosides
What occurs in protein synthesis initiation?
GTP hydrolysis activates initiation factors to assemble 40S with initiator tRNA
What occurs in protein synthesis elongation?
(1) Aminoacyl-tRNA binds to A site
(2) rRNA catalyzes peptide bonds, transfers aa to A site
(3) ribosome advances 3 nucleotides toward 3' end moving peptidyl RNA to P site
What occurs in protein synthesis termination?
completed protein is released via simple hydrolysis.
What are the eukaryotic ribosomal subunits?
40S + 60S = 80S
What are the prokaryotic ribosomal subunits?
30S + 50S = 70S
What are the roles of ATP and GTP in protein synthesis?
ATP- Activation of tRNA
GTP- Gripping/Going of tRNA (translocation)
What are the sequential sites on the ribosome in protein synthesis?
A site- incoming Aminoacyl tRNA
P site- Peptide growing site
E site- holds Empty/Exiting tRNA
"APE"
What is the moe of aminoglycosides?
inhibit the formation of the initiation complex and cause misreading of mRNA
What is the moe of chloramphenicol?
inhibits the 50S pepetidyltransferase
What is the moe of macrolides?
bind 50S, blocking translocation
What is the moe of clindamycin?
binds 50S, blocking translocation
What is the energy requirement of translation?
4 high-energy phosphoanhydride bonds
What is post-translational trimming?
Removal of N- or C-terminal propeptides from zymogens to generate mature protiens
What are some post-translational covalent alterations?
phosphorylation, glycosylation, and hydroxylation
What is post-translational involved in proteasomal degradation?
attachement of ubiquitin to defective proteins
What are the phase in the cell cycle?
Mitosis, G1, (G0), S, G2
Which is the shortest part of the cell cycle?
mitosis
What are the stages of mitosis?
prophase, metaphase, anaphase, telophase
What are the two common tumor suppressors?
Rb and p53 normally inhibit G1-S progression
What are some permanent cell types (remain in G0)?
Neurons, skeletal mm, cardiac mm, and RBCs
What are some stable cell types (enter G1 when stimulated)?
Hepatocytes, lymphocytes
What are some labile cell types (never go to G0)?
Bone marrow, gut epithelium, skin, and hair follicles.
What are the main functions of the RER?
Synthesis of secretory protiens, and N-linked oligosaccharide addition to proteins
What are Nissl bodies?
the RER in neurons- synthesize enzymes (ChAT) and peptide neuromodulators
What is the function of free ribosomes?
Synthesis of cytosolic and organellar proteins
What are some RER-rich cells?
Mucus-secreting goblet cells on small intestine and Ab-secreting plasma cells
What is the function of the SER?
Site of steroid synthesis and detoxification of drugs and poisons
What are some SER-rich cells?
Hepatocytes, and adrenal cortical steroid-hormone secreting cells
How are proteins targeted to lysosomes?
Golgi addition of mannose-6-phosphate
The golgi distributes?
protiens and lipids from ER to plasma membrane, lysosomes and secretory vesicles
The golgi modifies N-oligosaccharides on?
asparagine
The golgi takes protein cores and?
assembles proteoglycans with them, and sulfates the attached sugars.
The golgi sulfates?
proteoglycan sugars and selected tyrosine residues on proteins.
What is the function of COPI?
retrograde transport
Golgie --> ER
What is the function of COPII?
anterograde transport
RER --> cis-Golgi
What is the function of clathrin?
receptor-mediated endocytosis.
(trans-Golgi --> lysosomes, and plasma memb --> endosomes)
What is the defect in I-cell disease?
Failure of golgi-mediated addition of mannose-6-phosphate to lysosome proteins.
What is the pathophysiology of inclusion cell disease?
Lysomal enzymes are not targeted to lysosomes, and are secreted out of the cell instead.
What is the clinical presentation of I-cell disease?
Coarse facies, clouded corneas, restricted joint movement, high plasma lysosomal enzymes. Fatal in childhood.
What are the major functions of microtubules?
Flagella, cilia, mitotic spindles, and slow axoplasmic transport in neurons
What is the composition of a microtubule?
Dimers of alpha- and beta-tubulin with 2ATP bound to each, polymerized into helical array.
What are some drugs that act on microtubules?
Mebendazole, thiabendazole, griseofulvin, vincristine, vinblastine, paclitaxel, colchicine.
What is the function of dynein?
A molecular motor protein: retrograde transport to microtubule ( + to -)
What is the function of kinesin?
A molecular motor protein: anterograde transport to microtubule (- to +)
What is the defect in Chediak-Higashi syndrome?
Defective microtubule polymerizaion (decreased phagocytosis).
What is the clinical presentation in Chediak-Higashi syndrome?
Recurrent pyogenic infections, partial albinism, and peripheral neuropathy.
What is the composition of cilia?
9 +2 arrangement of microtubules
What is the function of axonemal dynein?
It is an ATPase linking the peripheral 9 doublets, differential sliding of the doublets causes cilia bending.
What is the defect in Kartagener's syndrome?
Immotile cilia due to a dynein arm defect
What is the clinical presentation of Kartagener's syndrome?
Male/female infertility, bronchiectasis, recurrent sinusitis.
What condition is associated with Kartagener's syndrome?
situs inversus
What are the functions of actin and myosin?
Form microvilli, muscle contraction, cytokinesis (post-mitosis pinch-off), adherens junctions.
What are the functions of intermediate filaments?
Form desmin, cytokeratin, glial fibrillary acid proteins, neurofilaments, and vimentin.
What is vimentin?
The dynamic structure of fibroblasts. Useful immunohisto marker for sarcoma.
What is defect/presentation of Alexander disease?
Altered glial fibrillary acid proteins, hence defective myelin sheaths. Phys/mental retard, dementia, large head/brain, spasticity, and seizures.
What are the main components of the lipid bilayer?
Cholesterol (~50%), phospholipids (~50%), sphingolipids, glycolipids, and proteins.
What is the effect of high cholesterol or long saturated fatty acid content in the lipid bilayer?
Increased melting temperature, decreased fluidity.
What does vimentin staining indicate?
connective tissue cells
What does desmin staining indicate?
muscle cells
What does cytokeratin staining indicate?
epithelial cells
What does GFAP staining indicate?
neuroglial cells
What does neurofilament staining indicate?
neurons
What is exchanged by the Na/K-ATPase?
3 Na+ go out
(ATP --> ADP)
2 K+ come in
What is the moe of ouabain?
it binds extracellularly to the K+ site of the Na/K-ATPase (inhibits pump)
What is the moe of cardiac glycosides?
Directly inhibit the Na/K-ATPase, indirectly inhibitting Na/Ca exchanger. Increased [Ca++] = increased contractility
Where is type I collagen found?
bone, skin, tendon, dentin, fascia, cornea, late wound repair
Where is type II collagen found?
Cartilage, vitreous body, nucleus pulposus
Where is type III collagen found?
Reticulin: skin, blood vessels, uterus, fetus, granulation tissue
Where is type IV collagen found?
Basement membranes or basal lamina
What are the six steps in collagen synthesis?
RER synthesis, ER hydroxylation, ER glycosylation, exocytosis, proteolytic processing, and cross-linking.
Describe RER synthesis of collagen?
Preprocollagen (alpha chains) translated, usually Gly-X-Y where X = proline, hydroxyproline, or hydroxylysine.
Describe ER hydroxylation of collagen?
Specific proline and lysine residues are hydroxylated
Describe ER glycosylation of collagen?
Pro-alpha-chain lysine residues are glycosylated, triple helical procollagen is formed
Outside the fibroblast, what happens to collagen?
Terminal region cleavage makes insoluble tropocollagen, covalent lysine-hydroxylysine cross-link makes collagen fibrils
What are the cofactors needed in collagen synthesis and formation?
Vitamin C (Pro and Lys hydroxylation in ER) and Cu++ (lysly oxidase crosslinkages to form fibrils)
What is the defect in Menkes disease?
Mutations in ATP7A, inability to transport copper into blood stream
What is the clinical presentation of Menkes disease?
Hypopigmentation, kinky hair, cerebral degeneration or hemorrhage, hypothermia, low serum Cu++ and ceruloplasmin.
What is the defect in Ehlers-Danlos syndrome?
Extracellular cleavage of terminal regions on procollagen is defective, can't form tropocollagen
Which collagen is most effected in Ehlers-Danlos syndrome?
collagen type III
What is the clinical presentation of Ehlers-Danlos syndrome?
Hyperextensible skin, bleeding/bruising, hypermobile joints.
What conditions are associated with Ehlers-Danlos syndrome?
Joint dislocation, berry aneurysms, organ rupture
What is the defect in osteogenesis imperfecta?
abnormal type I collagen (rich in glycine and proline)
What is the clinical presentation of OI tarda?
Multiple fractures w/min trauma, blue sclerae, hearing loss, dental imperfections
What is the mode of inheritance for OI tarda?
autosomal dominant
What is the clinical presentation in OI congenita?
fatality in utero or neonatal period
What is the incidence of osteogenesis imperfecta?
1:10,000
What is the defect in Alport's syndrome?
Variety of gene defects --> abnormal collagen type IV
What is the clinical presentation of Alport's syndrome?
nephritis, deafness and maybe ocular disturbances
What is the defect in Marfan's syndrome?
Defect in fibrillin, can't provide scaffolding for tropoelastin
What is the pathogenesis in alpha1-antitrypsin deficiency?
Elastase is not broken down, thus degrades elastin in the lungs, large arteries, ligaments, vocal cords, ligamentum flava
What product do you want in PCR?
An amplified specific DNA sequence
What is the blotting procedures acronym?
"SNoW DRoP"
Southern ssDNA
Northern ssRNA
Western Protein
Which blotting procedure do you use to evaluate DNA?
Southern
Which blotting procedure do you use to evaluate RNA?
Northern
What blotting procedure do you use to evaluate proteins?
Western blot
What can microarrays be used for?
To profile gene expression levels, or to detect SNPs (single nucleotide polymorphisms)
Which test is sensitive, and then which is specific when looking for Lyme disease?
ELISA (1st- very sensitive)
Western blot (2nd- v. specific)
What is FISH used for?
Localization of genes, and direct visualization of anomalies
What binds to what in FISH?
flour-in-situ-hybrid: DNA or RNA probe binds specific gene of interest
How does Sanger DNA sequencing work?
dideoxynucleotides halt DNA at each base, generates various length sequences. Electrophorese to deduce original sequence.
How is DNA cloned?
Insertion into abx resistant bacterial plasmids at 4-6 bp palindromic sequences, reverse transcriptase creates cDNA library (lacks introns)
What is pleiotropy?
When 1 gene has more than 1 effect on an individuals phenotype
What is imprinting?
the deactivation of either the maternal or paternal copy of a gene so only one is expressed
What is linkage disequilibrium?
When two alleles at linked loci to occur more frequently together than expected: measured in a population
What is lyonization?
random X inactivation in females
What is locus heterogeneity?
Mutations at different loci producing the same phenotype (marfanoid in Marfans, MEN 2B, and homocystinuria)
What is heteroplasmy?
Presence of normal and mutated mtDNA --> variable expression in inherited mitochondrial disease.
What is uniparental disomy?
Offspring recieves two copies of a chromosome from one parent, none from the other parent.
If in Hardy-Weinberg equilibrium, disease prevalence is?
p^2 + 2pq + q^2 = 1
If in Hardy-Weinberg equilibrium, allele prevalence is?
p + q = 1
If in Hardy-Weinberg equilibrium, what is the heterozygote prevalence?
2pq
If in Hardy-Weinberg equilibrium, the prevalence of x-linked disease is?
q in males and q^2 in females
Hardy-Weinberg equilibrium assumes?
1. No mutation at locus
2. No selection for mutant locus
3. Random mating
4. No migration
The defect in Prader-Willi is?
Imprinted maternal genes, and deletion of the active paternal genes on Chr 15 (or uniparental disomy)
The defect in Angelman's syndrome is?
Imprinted paternal genes, and deletion of the active maternal genes on Chr 15 (or uniparental disomy)
What is the clinical presentation of Prader-Willi syndrome?
Mental retardation, hyperphagia, obesity, hypogonadism, hypotonia
What is the clinical presentation of Angelman's syndrome?
"happy puppet". Mental retardation, seizures, ataxia, inappropriate laughter.
Who is affected by a x-linked recessive disease?
Sons of heterozygous mothers have 50% change
Who is affected by a x-linked dominant disease?
all female offspring of affected fathers are diseased
Who is affected in mitochondrial disease inheritance?
All offspring of affected mother may show signs of disease
What is the pathogenesis of Leber's hereditary optic neuropathy?
Degen of retinal ganglion cells and axons. Loss of vision, WPW syndrome, mt inheritance.
Achondroplasia: defect and presentation?
AD. Signal defect of FGFr3. Dwarfism (short limbs), asc'd w/paternal age
ADPKD: defect and presentation?
90% defective APKD1 Chr 16
Bilateral enlargement, flank AD. pain, htn, renal fail. Asc'd w/polycystic liver dz, BERRY ANEURYSMS, mitral valve prolapse. Infantile is recessive.
FAP: defect and presentation?
AD. Error in DNA repair. Adenomatous polyps after puberty --> cancer unless resected. Chr 5 deletion of APC gene.
Familial hypercholesterolemia: defect and presentation?
AD. Defect or absent LDL receptor. heterozy cholesterol ~300, homo ~700. MI maybe before 20, achilles or eyelid xanthomas, early atherosclerosis.
Hereditary hemorrhagic telangectasia: defect and presentation?
AD. Disorder of blood vessels. Telangectasia, recurrent epistaxis, skin discoloration, av malformations.
Hereditary spherocytosis: defect and presentation?
AD. Spheroid RBCs due to spectrin or ankrin defect. Hemolytic anemia, increased MCHC. Splenectomy curative.
Huntington's disease: defect and presentation?
AD. Chr 4 (CAG)x repeat disorder. Decreased GABA and ACh in brain, depression, prog demetia, chorieform mvmt, caudate atrophy.
Marfan's syndrome: defect and presentation?
AD. Fibrillin gene mutation. Tall, long extramities, arachnodactyly, cystic medial Ao necrosis, floppy mitral v, sublux of lenses.
Neurofibromatosis type 2: defect and presentation?
AD. NF2 gene on Chr 22. Bilateral acoustic neuroma, juvenile cateracts.
Tuberous sclerosis: defect and presentation?
AD. Adenoma sebaceum, 'ash leaf spots', corticol/retinal hamartomas, pheochromocytomas, cardiac rhabdomyomas, increase incidence of astrocytomas.
von Hippel-Lindau disease: defect and presentation?
AD. Deletion of VHL gene on Chr 3 causes constitutive expression of HIF trxn factor and activation of angiogenic GFs. Hemagioblastomas of retina/cerebellum/medulla, half dev. multiple bilateral renal cell carcinomas, et.
What is the defect in CF?
AR. Deletion of Phe at position 508 in CFTR gene on Chr 7. Defective Cl- channel--> secrete abnormally thick mucus
What is the clinical presentation of CF?
Recurrent pulm infx (s. aureus, pseudomonas), chronic bronchitis, bronchietasis, pancreatic insufficiency, meconium ileus
What is the effect of the deletion in cystic fibrosis?
Improper protein folding, channel degraded before reaching plasma membrane
What is the cause of infertility in cystic fibrosis affected males?
Absence of the vas deferens.
What deficiency might accompany CF?
ADEK fat-soluble vitamins
What is the most common lethal genetic disease in Caucasians?
cystic fibrosis
Who do you diagnose CF?
PCR of the Chr 7 mutation and/or? increased concentration of Cl- ions in the sweat
What is the treatment for CF?
N-acetylcysteine (cleaves disulfide bond in mucous glycoproteins)
Which are the X-linked recessive disorders?
Be Wise, Fools GOLD Heeds Silly Hope. Brutons agammaglobulinemia, Wiskott-Aldrich syndrome, Fabrys, G6PD deficiency, Ocular albinism, Lesch-Nyhan synd, Duchenne's/Beckers, Hunter's synd, Hemophilia A/B
What is the defect in Duchenne's muscular dystrophy?
X-linked frame shift mutation causing deletion of dystrophin gene
What is the clinical presentation of Duchenne's?
Pelvic girdle wkns, calf pseudohypertrophy, cardiac myopathy, under 5 yrs old, Gower's manuever
What is dystrophin important?
it anchors mm fibers in skeletal and cardiac muscle
What is the DMD gene suspectible to mutation?
the dystrophin gene is the longest known human gene
How do you diagnose muscular dystrophies?
increased CPK and mm biopsy
What is the defect in Becker's muscular dystrophy?
x-linked mutated dystrophin gene, is less severe than not having gene at all
What is the defect in fragile X?
X-linked defect affecting methylation of FMR1 gene (asc'd w/chr breakage) (CGG)x repeats
What is the clinical presentation of Fragile X syndrome?
Long face, long jaw, macroorchidism, large everted ears, autism, mitral prolapse.
What are the trinucleotide expansion diseases?
Huntington's disease, Myotonic dystrophy, Friedrich's ataxia, fragile X syndrome (Hunting for My Friend Xavier)
Which condition has (CAG)x repeats?
Huntington's disease
Which condition has (CTG)x repeats?
Myotonic dystrophy
Which condition has (CGG)x repeats?
fraGile x
Which condition has (GAA)x repeats?
Friedrich's ataxia
What is the incidence of trisomy 21?
1:700
What is the incidence of trisomy 18?
1:8,000
What is the incidence of trisomy 13?
1:15,000
What are some clinical findings in trisomy 21?
Ment retard, epicanthal folds, simian crease, flat facies, 1st-2nd toe gap, duodenal atresia, congenital heart disease (s primum ASD)
What conditions are associated with Down's syndrome?
Alzheimers and increased risk of ALL (acute lymphoblastic leukemia)
What is the main cause of the most common chromosomal disorder?
95% non-disjunction of homologous chr (trisomy 21)
What is the effect of advanced maternal age on trisomy 21?
Over 45 yrs 1:25 incidence (only 1:1,500 when mother is 20 yo)
What are non-nondisjunction causes of trisomy 21?
4% Robertsonian translocation
1% Down mosaicism
What is the most common cause of congenital mental retardation?
Down's - trisomy 21
How is Trisomy 21 reflected in the quad screen?
Decreased alpha-FP, and estriol.
Increased b-HCG, and inhibin A.
What is the clinical presentation of trisomy 18?
severe mental retard, rocker-bottom feet, micrognathia, low set ears, clenched hands, prominent occiput, congenital heart disease, death by 1 yo
What is the clinical presentation of trisomy 13?
severe mental retard, rocker-bottom feet, micropthalmia, cleft lip/palate, holoproencephay, polydactyly, congenital heart disease, death by 1 yo
What are the names of trisomy 21, 18, and 13 respectively?
Downs, Edwards, Patau's
If nondisjunction of chr 21 occurs at anaphase I, what are the chances of offspring being affected?
100%
If nondisjuntion of chr 21 occurs at anaphase II, what are the chances of offspring being affected?
25%--- well?? maybe 1/3 so 33%?
What is Robertsonian translocation?
Long arms of 2 acrocentric chromosomes fuse, and short arms are lost
Which chr are involved in Robertsonian translocations most often?
13, 14, 15, 21, 22
What is a possible result in chromosomal inversions?
decreased fertility
Which type of chromosome inversion is worse?
Probably pericentric (involves centromere) because it proceeds through meiosis.
What is the defect in Cri-du-chat syndrome?
Congenital microdeletion of short arm of chr 5
What are the findings in Cri-du-chat syndrome?
Microcephaly, mod-severe mental retard, high pitched crying, epicanthal folds, cardiac abnormalities
What is the defect in William's syndrome?
Microdeletion in long arm of chr 7 (includes elastin gene)
What are the findings in William's syndrome?
Ment retard, 'elfin' facies, increased sens to Vit D (hypercalcemia), well-dev'd verbally, extremely friendly w/strangers, CV abnormalities
What is the defect in 22q11 deletion syndromes?
Aberrant development of the 3rd and 4th branchial pouches
DiGeorge syndrome: defect and presentation?
22q11 deletion. thymic aplasia, cardiac defects, hypocalcemia
Velocardiofacial syndrome: defect and presentation?
22q11 deletion. cleft palate, abnormal facies, cardiac defects
Fat soluble vitamins, and place of absorption?
ADEK- absorbed in ileum w/help of pancreas
Other names for B1?
Thiamine
TPP (thiamine pyrophosphate-active)
Other names for B2?
Riboflavin
FAD
FMN
Other names for B3?
Niacin
NAD+
Nicotinamide
Other names for B5?
Pantothenic acid
CoA
Other names for B6?
Pyridoxine
PLP (pyridoxal phosphate)
Other name for B12, and unique mineral it contains?
Cobalamin -contains selenium
Other name for Vit C?
Ascorbic acid
Other name for B7?
Biotin
Other name for B9?
Folate
Which water soluble vitamins have bodily stores?
B12 (6-7 years)
Folate (3-4 months)
B-complex deficiencies often result in what three presenting symptoms?
Dermatitis, glossitis, and diarrhea
Vitamin A is essential for differentiation of epithelial cells in to which specialized cells?
-pancreatic cells
-mucus-secreting cells
What are the sequelae of vit A deficiency?
Night blindness, dry skin, squamous metaplasia w/ corneal opacification
What occurs in Vit A toxicity?
Arthralgias, fatique, HA, skin changes, sore throat, alopecia, teratogenic (cleft palate, cardiac abnormalities)
What four major enzymes require B1 as a cofactor?
Pyruvate dehydrogenase, a-ketoglutarate, transketolase, branched chain aa dehydrogenase
What results from B1 deficiency?
Wernicke-Korsakoff, Dry/Wet Beriberi
How does Wernicke-Korsakoff present?
confusion, ophthalmoplegia, ataxia, memory loss, confabulation, personality change
What is the function of B2?
Cofactor in oxidation/reduction (FAD/FMN) --> riboFLAVIN
How does a deficiency in B2 present?
Cheilosis, corneal vascularization
What is the function of Vit B3?
Redox rxn (NAD+, NADP+ constituent)
What is Vit B3 derived from?
tryptophan
How many ATP are in niacin?
3
How many ATP are in riboflavin?
2
How does a deficiency of B3 present?
Glossitis, if severe then; pellagra
What can cause severe B3 deficiency?
Hartnup disease, malignant carcinoid syndrome, INH treatment.
What are the 3 D's of B3 deficiency?
Diarrhea, Dermatitis, Dementia
How does B3 excess present?
Facial flushing
What is the function of B5?
essential component of CoA and fatty acid synthatse
How does a B5 deficiency present?
Dermatitis, enteritis, alopecia, adrenal insufficiency
What are the functions of B6?
Cofactor in transamination, decarboxylations, glycogen phosphorylase, cystathionine synthase, heme synthesis, synthesis of niacin.
How does B6 deficiency present?
Convusions, hyperirritability, peripheral neuropathy, sideroblastic anemias
What can induce B6 deficiency?
INH or oral contraceptive usage
What is the molecular function of B12?
Cofactor for homocysteine methyltransferae and methylmalonyl-CoA mutase.
What is the presentation of a cobalamin deficiency?
Macrocytic megaloblastic anemia, hypersegmented PMNs, neuro (paresthesias, subacute combined degen)
What is the dietary source for B12?
animal products
Is there a reserve pool for B12 in the body?
Several years worth in the liver
What are the main causes of cobalamin deficiency?
1. Malabsorption (sprue, diphyllobothrium)
2. Lack of IF
3. Absence of terminal ileum
What is the Schilling test?
Give labeled B12. If less than 10% in urine, give with intrinsic factor.
What is the molecular function of folic acid?
Conversion to tetrahydrofolate for 1-C/methylation transfer reactions (especially nitrogenous bases in DNA/RNA)
What is the presentation of folic acid deficiency?
Macrocytic megaloblastic anemia (neuro is fine)
When are folate deficiencies seen?
Pregnancy, alcoholism, phenytoin, sulfonamides, MTX
What is the role of S-adenosyl-methionine?
ATP + methionine = SAM
Converts NE to Epi.
What cofactors are required to convert NE to Epi?
S-adenosyl-methionine requires B12 and folate to convert NE to Epi.
What is the molecular function of biotin?
Cofactor for carboxylation enzymes
What reactions require biotin?
Decarboxylase

1. pyruvate carboxylase --> oxaloacetate
2. acetyl-CoA carboxylase --> malonyl-CoA
3. propionyl-CoA carboxylase --> methylmalonyl-CoA
What is the presentation of a biotin deficiency?
Dermatitis, alopecia, enteritis
What can cause a biotin deficiency?
antibiotic use or excessive raw eggs (avidin avidly binds biotion)
What are the roles of ascorbic acid?
1. Antioxidant
2. Keeps Fe2+ reduced for absorption
3. Needed for Proline and lysine hydroxylation in collagen synthesis
4. Necessary for dopamine beta-hydroxylase conversion of dopamine to NE
What is the presentation of Vitamin C deficiency?
Scurvy: swollen gums, bruising, anemia, poor wound healing
What is the storage form of Vitamin D?
25-hydroxycholecalciferol
What is the active form of Vitamin D?
1,25-(OH)2 D3 Calcitriol
What is the presentation of vitamin D deficiency?
Hypocalcemic tetany
Adults- osteomalacia
Kids- rickets
What clinical signs can be elicited in vitamin D deficiency?
Troussou- carpal spasm w/BP cuff Chovstak- tap face elicits facial spasm
What form of vitamin D is ingested from plants?
D2 Ergocalciferol
What form of vitamin D is ingested from milk, or son exposed skin?
D3 Cholecalciferol
What is the function of vitamin E?
Antioxidant (especially erythrocytes and cell membranes)
What is the presentation of vitamin e deficiency?
Hemolytic anemia (increased erythrocyte fragility), mm weakness, neurodysfunction
What is the function of vitamin K?
Catalyzes gamma-caboxylation of glutamic acid residues on clotting proteins
What is the presentation of vitamin K deficiency?
Neonatal hemorrhage with increase PT, and aPTT, but normal bleeding time.
-Also with prolonged abx use
Vitamin K is necessary for the synthesis of which clotting factors?
II, VII, IX, X, protein C and S
What is a vitamin K antagonist?
Warfarin
What is the molecular function of zinc?
Formation of zinc fingers (transcription factor motiff), and the activity of 100s of enzymes
What is the presentation of a zinc deficiency?
Delayed wound healing, hypogonadism, decreased adult hair, dysgeusia, anosmia, predisposition of etOH cirrhosis
What is the sequence of ethanol metabolism?
Ethanol (alcohol dehydrogenase) --> Acetylaldehyde (acetylaldhyde dehydrogenase) --> Acetate
What is the limiting reagent in ethanol metabolism?
NAD+
What does fomepizole inhibit?
alcohol dehydrogenase in the cytoplasm
What does disulfiram inhibit?
acetaldehyde dehydrogenase in mitochondria
(accumulation contributes to hangover)
How does alcohol dehydrogenase operate?
zero order kinetics
What causes ethanol hypoglycemia?
Ethanol metabolism increases NADH/NAD+ liver ratio, shuntin pyruvate to lactate and oxaloaceteate to malate, inhibiting gluconeogenesis and stimulated FA synthesis
Kwashiorkor
Protein malnutrition
Protein deficient MEAL: malnutrition, edema, anemia, fatty liver
Marasmus
energy malnutrition--> muscle wasting
What metabolism occurs in the mitochondria?
FA oxidation, acetyl-CoA production, TCA cycle, oxidative phosphorylation
What metabolism occurs in the cytoplasm?
Glycolysis, FA synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER)
What reactions metabolize in the cytoplasm and mitochondria?
Heme synthesis, Urea cycle, Gluconeogenesis
"HUGs take two (locations)."
What does a glucokinase do?
Catalyzes the phosphorylation of glucose using one ATP
What does a kinase do?
Uses ATP to phosphorylate substrates
What does a phosphorylase do?
Adds inorganic phosphate to substrate w/o using energy
What does a phosphatase do?
Removes phosphate group from substrate
What does a carboxylase do?
Adds 1 carbon with the help of biotin
What is the rate determining enzyme of glycolysis?
phosphofructokinase-1 (PFK-1)
What is the rate determining enzyme of gluconeogenesis?
fructose-1,6-bisphosphatase
What is the rate determining enzyme of the TCA cycle?
isocitrate dehydrogenase
What is the rate determining enzyme of glycogen synthesis?
glycogen synthase
What is the rate determining enzyme of glycogenolysis?
glycogen phosphorylase
What is the rate determining enzyme of the HMP shunt?
glucose-6-phosphate dehydrogenase (G6PD)
What is the rate determining enzyme of de novo pyrimidine synthesis?
carbamoyl phosphate synthetase II
What is the rate determining enzyme of de novo purine synthesis?
glutamine-PRPP amidotransferase
What is the rate determining enzyme of the urea cycle?
carbamoyl phosphate synthetase I
What is the rate determining enzyme of fatty acid synthesis?
acetyl-CoA carboxylase (ACC)
-requires biotin
What is the rate determining enzyme of fatty acid oxidation?
carnitine acyltransferase I
What is the rate determining enzyme of ketogenesis?
HMG-CoA synthase
What is the rate determining enzyme of cholesterol synthesis?
HMG-CoA reductase
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