Genetics and Molecular Biology Concepts, Exams of Biochemistry

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CBSE BIOCHEM Exam With Complete Questions And

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Lesch-Nyhan Syndrome: what causes it and what are manifestations? Correct Answer: HGPRT deficiency in purine salvage pathway (this enzyme normally converts hypoxanthine to IMP and guanine to GMP). This deficiency leads to excessive Uric acid production and de novo purine synthesis. It is X linked recessive. Symptoms: hyperuricemia, gout, aggression / self mutilation, mental retardation, dystonia. Treatment for Lesch-Nyhan? Correct Answer: Allopurinol / febuxostat second line. Both of these drugs inhibit xanthine oxidase, which converts hypoxanthine to xanthine and xanthine to uric acid. Adenosine Deaminase Deficiency: what is it, what effects does it have? Correct Answer: ADA is required for degradation of adenosine and deoxyadenosine--dATP builds up and is toxic to lymphocytes, which is why this disease is a major cause of SCID--severe combined immunodeficiency (Autosomal recessive). Why is purine salvage important? Correct Answer: Because in some tissues, de novo purine synthesis is not possible. How are nucleotide monophosphates created? Correct Answer: Activated ribose- 5 - phosphate (PRPP) is added to bases by phosphoribosyltransferases (HGPRT and APRT are the two types of this enzyme). tRNA Wobble: what is it and it causes which type of mutation? Correct Answer: An unusual pairing of bases in the third position of the codon--causes silent mutation. Sickle Cell Anemia is caused by which type of mutation? Correct Answer: Missense mutation--valine replaces glutamic acid. Tay-Sachs and Duchenne Muscular Dystrophy are caused by which mutation type? Correct Answer: Frameshift Xeroderma Pigmentosum: is caused by a defect in what specifically? Correct Answer: Nucleotide excision repair--pyrimidine dimers are not repaired (caused by UV exposure). In nucleotide excision repair, bulky helix-disturbing lesions are repaired by endonucleases. This occurs during G1 of cell cycle. How is spontaneous / toxic deamination repaired? Correct Answer: Base excision repair--involves AP endonucleases throughout the cell cycle What is defective in Lynch Syndrome? What is another term for Lynch Syndrome? Correct Answer: Lynch syndrome= hereditary nonpolyposis colorectal cancer. Mismatch repair is defective. This usually occurs in G2 of cell cycle. What is the underlying pathology in Fanconi Anemia and Ataxia Telangiectasia? Correct Answer: Mutation in nonhomologous end joining (repairs double stranded breaks).

What is the mRNA start codon and what does it code for in prokaryotes, eukaryotes? Correct Answer: AUG--codes for methionine in eukaryotes, N-formylmethionine in prokaryotes What are the mRNA stop codons? Correct Answer: UGA, UAA, UAG What sequences are common in gene promoters? What binds at the promoter? Correct Answer: AT- rich sequences and TATA and CAAT boxes. RNA pol II and other transcription factors bind to promoter. What does promoter mutation commonly result in? Correct Answer: Decrease in gene transcription Alpha-aminitin Correct Answer: Found in death cap mushrooms. Inhibits RNA pol II--severe hepatotoxicity if ingested Rifampin Correct Answer: Inhibits RNA pol in prokaryotes Actinomycin D (Dactinomycin) Correct Answer: Inhibits RNA pol in eukaryotes and prokaryotes What happens to form mRNA? Correct Answer: HnRNA is immature, and is what is first transcribed by RNA pol II. 5' capping with methylguanosine, 3' adenylation (poly A tail), and splicing out of introns all occur in order to make mature mRNA. How does splicing occur and what diseases are effected by splicing abnormalities? Correct Answer:

1. Primary transcript joins snRNPs to make spliceosome. 2. Lariat loop is formed and 3. Lariat (intron) is cut out to join 2 exons together. In SLE, anti-Smith antibodies are antibodies to spliceosomal snRNPs. In MCTD (mixed connective tissue disease), antibodies against U1-RNPs are found. What do microRNAs (miRNAs) do? Correct Answer: Post-transcriptional regulation of gene expression. They target mRNA and degrade / inactivate certain sequences identified by complimentary base pairing. This is a mechanism by which cancer begins! MiRNAs inactivate tumor suppressor genes. tRNA (transfer RNA) has a defining sequence at one of its ends- what is that sequence and what is the significance of that end? Correct Answer: The sequence is CCA at the 3' end, and this end is where the amino acid is covalently bound. The amino acid acceptor site is 5'-CCA-3' What are the three arms of tRNA? What are their functions and what are they composed of? Correct Answer: T arm, D arm and acceptor stem. T arm: site of tRNA ribosomal binding. Contains ribothymidine, pseudouridine, and cytidine. D arm: site of recognition by aminoacyl synthetase. Contains dihydrouridine. Acceptor stem: 5'-CAA-3'. What is "charging" in the context of tRNA, how does it occur, and what is the significance of the energy exchanged? Correct Answer: Charging is the process of loading an amino acid onto the acceptor stem of tRNA. The enzyme that does this is aminoacyl tRNA synthetase and an ATP is used to create this bond. The energy of this bond will be used to create the peptide bond* What are the ribosomal subunits involved in prokaryotic and eukaryotic protein synthesis? Correct Answer: Eukaryotes-- 40s + 60s--> 80s. Prokaryotes: 30s + 50s --> 70s

What is translocation and what is its energy source? Correct Answer: "Initiation" or Translocation is the process whereby initiation factors (IFs) assemble the 40s ribosomal subunit and initiator tRNA. IFs are released when this complex joins with the 60s / mRNA. This process uses GTP for energy. **Remember, charging uses ATP for energy. Charging is the loading of the tRNA with the amino acid. What are the three phases of protein translation? Correct Answer: Initiation (translocation), elongation, termination Describe elongation (protein synthesis) Correct Answer: 60s subunit has 3 sites: A, P, E. Aminoacyl- tRNA enters A site. Ribozyme (rRNA) catalyzes formation of peptide bonds, and growing polypeptide is transferred to aa in A site. The ribosome advances 3 nucleotides towards 3' end of the mRNA, which moves the next peptidyl tRNA to the P site. E site is where empty tRNA is held before being released. Describe the process of termination Correct Answer: The stop codon is recognized by release factor and protein synthesis stops. What are the common post-translational modifications and what happens in each? Correct Answer: Trimming and covalent alterations. Trimming: N or C termini are cleaved from zymogen to yield mature protein (example is trypsinogen --> trypsin). Covalent alterations include: acetylation, hydroxylation, ubiquitination, methylation, glyocosylation, phosphorylation. What is heat shock protein (hsp60) and what is it an example of? Correct Answer: In yeast, hsp prevents desaturation of proteins at high temps. This is an example of a CHAPERONE protein--which facilitations or maintains folding of proteins intracellularly. What are the major cell cycle regulators? How do they work and interact with one another? Correct Answer: Cyclins, CDKs, tumor suppressors. Cyclins activate CDKs, which are constitutive and inactive by default. These cyclin-CDK complexes phosphorylate other proteins to regulate the cell cycle and control its progression. At times these complexes must be activated and at others they must be inactivated for proper cell cycle progression. The general tumor suppressor pathway: p induces p21, which inhibits CDKs, leading to the hypophosphorylation of Rb and its activation. Rb then inhibits E2F, thereby inhibiting the G1--> S transition. E2F is a transcription factor. **INHIBITION OF THESE GENES RESULTS IN UNCONTROLLED CELL GROWTH. THIS IS THE CASE IN LI FRAUMENI SYNDROME FOR EXAMPLE. Permanent cell types: what are they and what are some examples? Correct Answer: These remain in G0 and can only regenerate from stem cells. Examples include neurons, skeletal and cardiac muscle, and RBCs. Quiescent (stable) cell types: what are they and what are some examples? Correct Answer: These remain in G0 until stimulated to enter G1. Examples include lymphocytes and hepatocytes. Labile cell types: what are they and what are some examples? Correct Answer: These are continuously dividing--they never go to G0, and progress straight to a short G1. Skin, gut epithelium, germ cells, hair follicles, bone marrow are all examples. Which cell type is most affected by chemotherapy? Correct Answer: Labile cells!

What does RER do? Correct Answer: Synthesizes secretory proteins and performs N-linked oligosaccharide addition. What is a Nissl body and what does it do? Correct Answer: Nissl bodies are RER in neurons. They secrete peptide neurotransmitters for secretion. What do free ribosomes make? Correct Answer: Proteins for cytosol and organelles. What cell types are rich in RER? Correct Answer: Mucous-secreting goblet cells of the small intestine and antibody-secreting plasma cells. What does SER do and where is SER heavily concentrated? Correct Answer: SER synthesizes steroids and detoxes poisons and drugs. It is common in liver hepatocytes and adrenals / gonads (these last two make steroid hormones!) What does the Golgi apparatus do? Correct Answer: It modifies N-linked oligosaccharides on asparagine and adds O-linked oligosaccharides to serine and threonine. It also adds mannose- 6 - phosphates to proteins destined for lysosomes. What do endosomes do? Correct Answer: They are the organizing centers of the cell for things that are brought in from extracellular environment and also for vesicles from the golgi. It packages and sends things either to lysosomes, back to golgi, or to membrane, etc. What is I cell disease? What other names does it go by? Correct Answer: Inclusion cell disease / mucolipidosis type II. It is an inherited lysosomal storage disorder. It is caused by a defect of N- acetylglucosaminyl- 1 - phosphotransferase, which results in the inability to phosphorylate mannose residues-->Things that were supposed to go into lysosomes can't anymore and instead get secreted, resulting in high plasma levels of lysosomal proteins. Results in clouded corneas, joint immobility, coarse facial features, and often death in childhood* What are Signal Recognition Proteins? Correct Answer: These deliver proteins made by free ribosomes to the RER. These are abundant and they are ribonucleoproteins. Defect in these causes protein build-up in the cytosol. What is COPI? Correct Answer: It is a vesicular transport protein involved in retrograde movement: golgi-->cis golgi (faces the ER)--> ER What is COPII? Correct Answer: Vesicular transport protein involved in anterograde movement between ER and golgi: ER--> cis golgi What is Clathirin? Correct Answer: A vesicular transport protein involved in movement of trans golgi vesicles to lysosomes or PM, and from PM to endosomes -- INVOLVED IN RECEPTOR-MEDIATED ENDOCYTOSIS (LIKE LDL RECEPTOR ACTIVITY). Trans golgi faces away from the ER and towards the plasma membrane (think Trans=transplant away!) What happens in peroxisomes? Correct Answer: Catabolism of very long chain FAs via beta- oxidation, branched chain FAs, AAs, and ethanol. What is a proteasome and what happens there? What disease has been linked to issues with proteasomes? Correct Answer: It is a barrel shaped protein complex that destroys damaged or

ubiquitin-tagged proteins. Parkinson's has been linked to defects in the ubiquitin-proteasome complex. What is the primary role of microfilaments? What are examples of these filaments? Correct Answer: Cytokinesis and muscle contraction. Actin, microvilli are examples. What is the primary role of intermediate filaments? What are some examples? Correct Answer: Maintain cell structure. Some examples are vimentin, desmin, glial fibrillary acid protein (GFAPs), cytokeratin, neurofilaments, lamins What is the primary role of microtubules? What are some examples? Correct Answer: These are involved in movement and cell division. Examples include mitotic spindle, cilia, flagella, centrioles, axonal trafficking. What is vimentin, and what does the immunohistological marker for vimentin denote? Correct Answer: It is an intermediate filament of mesenchymal tissue, such as fibroblasts, endothelium, macrophages. Staining denotes mesenchymal tumors (sarcomas) but also other tumors such as endometrial carcinoma, renal cell carcinoma, and meningiomas What is GFAP, and what does it stain for? Correct Answer: It is the intermediate filament for neuroglia (Schwann, glial cells, astrocytes). Its staining represents glial tumors, like glioblastoma and astrocytoma. What is desmin and what does it stain for? Correct Answer: It is the intermediate filament for muscle. Stains for muscle tumors like rhabdomyosarcoma. What is cytokeratin and what does it stain for? Correct Answer: It is the intermediate filament for epithelial cells and stains for squamous cell carcinoma and other epithelial tumors. What are neurofilaments and what do they stain for? Correct Answer: They are intermediate filaments for neurons and they stain for neuronal tumors such as neuroblastoma. What are microtubules composed of and what are the characteristics of its assembly and degradation? Correct Answer: Cylinder of alpha and beta tubulin heterdimers--each dimer has 2 GTPs associated. MTs grow slowly but collapse quickly. Which drugs act on microtubules? Correct Answer: Vincristine / vinblastine (anti-cancer), paclitaxel (anti-cancer), colchicine (anti-gout), griseofulvin (anti-fungal), mebendazole (antihelminthic) What are the two molecular motor proteins and in what direction does each transport its cargo? Correct Answer: Kinesin: anterograde, so towards + end of MT. Dynein: retrograde, so towards - end of MT. How are cilia structured? What protein causes them to move? Correct Answer: 9+2 arrangement of MT doublets. At the base below membrane there is a basal body that has 9 MT triplets. Axonemal dynein is the ATP-ase that causes the 9 MTs to come together to create sliding movement and therefore motion. What is Kartagener's syndrome? What causes it, and what are its effects? Correct Answer: AKA primary ciliary dyskinesia. It's caused by a defect in the dynein arm--> immobile cilia. This causes

infertility in men and women because in men, sperm are immotile and in women, cilia of the Fallopian tube don't work (results in higher risk of pregnancy!). Also causes bronchiestasis, chronic sinusitis, and situs inversus (dextrocardia on CXR). What do fungal plasma membranes possess? Correct Answer: Ergosterol. Describe the Na+-K+ ATPase Correct Answer: ATP binds on the cytosolic side, phosphorylating the enzyme and causing release of 3 Na+ out of the cell. When the protein becomes dephosphorylated, 2 K+ come back into the cell. Ouabain: what does it inhibit and what does it cause? Correct Answer: It binds to the K+ site of the Na/K ATPase and therefore inhibits it. High IC calcium--> increased contractility. Cardiac glycosides: what do they inhibit and what do they cause? Correct Answer: Digoxin and digitoxin are the two glycosides. These directly inhibit the ATPase. These indirectly inhibit the Na/Ca exchange pump, thereby causing a high IC build-up of Ca2+ and therefore increase cardiac contractility. What is the most abundant protein in the body and what does it do? Correct Answer: Collagen and it organizes and strengthens the ECM Collagen Type I: Correct Answer: Bone, dentin, skin, tendon, fascia, late wound repair, cornea Collagen Type II: Correct Answer: Cartilage, vitreous body and nucleus pulposus Collagen Type III: Correct Answer: Reticulin: blood vessels, skin, fetal tissue, uterus, granulation tissue Collagen type IV: Correct Answer: Basement membrane, basal lamina and lens. Which collagen type is most abundant? Correct Answer: Type I-- is 90% of all collagen in the body What causes osteogenesis imperfecta? Correct Answer: Low production of type I collagen What can type III collagen deficiencies cause? Correct Answer: The vascular type of Ehlers-Danlos (less common type) What do type IV collagen defects cause? Correct Answer: Alport syndrome and they are targeted by autoantibodies in goodpasture syndrome. What are the general steps of collagen synthesis? Correct Answer: Synthesis, hydroxylation, glycosylation, exocytosis, proteolytic cleaving, and cross linking. What happens during collagen synthesis? Correct Answer: Alpha collagen (preprocollagen) is formed with sequence GLY-X-Y, where X and Y are proline or lysine. Collagen is made mostly of which amino acid? Correct Answer: Glycine-- it is 1/3 glycine!

What happens during hydroxylation? What disease occurs if there is a problem here? Correct Answer: Hydroxylation of certain proline / lysine residues. This requires Vit C-- deficiency causes scurvy! What happens during glycosylation? What disease occurs if there is a problem here? Correct Answer: Procollagen is formed via hydrogen and disulfide bonds to make triple alpha helix. Glycosylation of hydroxylated residues on pro-alpha-collagen chain occurs first. **Defect in forming the triple helix causes osteogenesis imperfecta! What happens during proteolytic processing? Correct Answer: Insoluble tropocollagen is made via the cleavage of disulfide-rich terminal regions of the procollagen What happens during cross-linking? What do problems here result in? Correct Answer: Cross-linking of staggered tropocollagens via covalent lysine-hydroxylysine cross-linkage (copper containing Lysol oxidase). **This makes collagen fibrils and problems at this step cause Ehlers-Danlos and Menkes Disease. Brittle Bone Disease Correct Answer: Most common form in autosomal dominant and involves low production of otherwise normal type I collagen due to COLIA1 and COLIA2 gene defects. Symptoms include: blue sclera, bones that break easily, hearing loss, dentinogenesis imperfecta (opalescent teeth) due to lack of dentin. Ehlers-Danlos Syndrome overview: what are the three types? Correct Answer: Ehlers-Danlos is caused by faulty collagen synthesis. There is the HYPERMOBILE type: this is the most common type and causes joint instability. There is the VASCULAR type: berry / aortic aneurysms and organ rupture--this is caused by mutation in type III collagen. There is the CLASSICAL type: joint and skin manifestations caused by mutation in type V collagen. E-D can be AD or AR, and the overall symptoms include: hyper flexible skin and mobile joints that dislocate easily, a tendency to bleed and bruise, berry and / or aortic aneurysms, organ rupture. Menkes disease Correct Answer: XLR CT disease caused by a defect in Menkes protein (ATP7A) which leads to IMPAIRED COPPER ABSORPTION AND TRANSPORTATION. Remember--copper is a necessary cofactor for Lysyl oxidase, which stabilizes collagen fibrils. This leads to brittle, 'kinky' hair, growth retardation, and hypotonia. Describe the structure of elastin, its composition, and what diseases are related to it? Correct Answer: It's made of glycine, non hydroxylated proline and lysine residues (similar to collagen!). It is made from tropoelastin with fibrillin scaffolding. It is cross-linked extracellularly, which is what gives it its elasticity. It is broken down by elastase, which is inhibited by alpha- 1 - antitrypsin. The two diseases are emphysema and Marfan's. What is the cause of emphysema? Correct Answer: Alpha- 1 - antitrypsin deficiency: excessive elastase activity. What is the cause of Marfan syndrome? Correct Answer: Defect in fibrillin, which is a glycoprotein forming a sheath around elastin. What is the usefulness of PCR and what is the basic process? Correct Answer: It is useful for diagnosis. You want to amplify a certain segment of DNA. The desaturation at 95 degrees separates

the strands. Annealing at 55 degrees allows the primers to bind onto targets. Elongation at 72 degrees allows heat stable DNA polymerase to elongate the strand. The cycles then repeat. Southern blot Correct Answer: Identifies DNA segments using radiolabeled probes, gel electrophoresis and a filter (after cleaving the DNA pieces into little fragments). Northern Blot Correct Answer: Identifies RNA in a process similar to the Southern blot, except RNA is electrophoresed. **USEFUL FOR STUDYING GENE EXPRESSION VIA LOOKING AT mRNA LEVELS. Western Blot Correct Answer: Sample protein separated by gel electrophoresis. Target protein is transferred to a membrane and a labeled antibody is used to find a specific protein. **THIS IS THE CONFIRMATORY TEST FOR HIV AFTER A +IVE ELISA TEST. How is HIV usually diagnosed? Correct Answer: ELISA --> Western blot (if ELISA +(ive)) Southwestern blot Correct Answer: IDs DNA-binding proteins with labeled oligonucleotide probes. Describe flow cytometry--the basics of the process and the purpose of using it Correct Answer: Cells are tagged with fluorescent antibodies and a laser counts them. The results are plotted on a histogram. This technique is used to identify size, granularity and protein expression of individual cells-->used clinically in the work up of hematologic abnormalities (HIV, paroxysmal nocturnal hemoglobinura, fetal RBCs in mother's blood, etc.) What are microarrays used for? Correct Answer: Thousands of DNA or RNA sequences are arranged on a grid and a DNA or RNA probe is hydridized and analyzed by a scanner. This is useful in detecting SNPs, CNVs, etc for the purpose of genotyping, genetic testing, forensic analysis, cancer mutation and genetic linkage analysis. ELISA test Correct Answer: Used to ID specific antigens or antibodies. An antibody is linked to a protein and applied to the sample. The protein is capable of undergoing some reaction with an added substrate (like a color change), thereby denoting the presence of the antibody or antigen in question. Can be highly sensitive and specific. On what tissues can karoytyping be performed, and for what purpose? Correct Answer: Bone marrow, placental tissue, amniotic fluid, and blood. It is used for the purpose of identifying chromosomal imbalances, etc. Fluorescence in situ hybridization Correct Answer: A fluorescent DNA or RNA probe binds specific gene site of interest. This test shows microdeletions (no fluorescence on one chromosome but +ive on the homologous), translocation (it lights up outside the chromosome of interest) or duplications (it lights up twice on one chromosome relative to its homologous). Describe the process of cloning Correct Answer: Creates a recombinant DNA molecule that is self- perpetuating. A fully processed mRNA sequence if exposed to reverse transcriptase to form cDNA, which does not have introns. This is then inserted into bacterial plasmids containing antibiotic resistance genes, and the plasmid is transformed into bacteria. The bacteria surviving on the antibiotic medium contain the recombinant plasmid.

What does the cre lox do and study? Correct Answer: Manipulates genes at specific developmental points, for example: to study a gene that causes embryonic death. RNAi--what is it and what is it used for? Correct Answer: double stranded RNA is synthesized complementary to mRNA of interest. When dsRNA is injected into cells, the strands separate and cause destruction, or "knocking down" of mRNA in question. Codominance examples: Correct Answer: Blood groups and alpha- 1 - antitrypsin deficiency. Both alleles contribute to phenotype. Variable expressivity examples: Correct Answer: Same disease genotype manifests in varying severity. For example, two patients with neurofibromatosis I have different severities of the disease. incomplete penetrance Correct Answer: A gene not necessarily expressed in the phenotype all the time: for example, not everyone with BRCA1 mutation gets ovarian or breast cancer. Pleiotropy example Correct Answer: One gene causes multiple phenotype genes effect: phenylketonuria causes light skin, musty body odor and intellectual disability. Anticipation example Correct Answer: Increasing severity and / or earlier onset in successive generations with a disease. An example is Huntington's disease. Loss of heterozygosity example Correct Answer: If a patient inherits or develops a mutation in a TUMOR SUPPRESSOR GENE, they must lose the complementary allele in order for cancer to develop. Retinoblastoma is an example of this "double hit" hypothesis. Lynch syndrome and Li Fraumeni are also examples of this. Dominant Negative Mutation example Correct Answer: The heterozygote has a mutation that disrupts the functioning of the normal allele as well. An example would be the mutation of a transcription factor in its allosteric site. Although there is still one normal TF, the mutant TF will bind to the site and block the action of the normal allele. Linkage disequilibrium Correct Answer: The tendency for 2 alleles at separate but linked loci to occur together more than would be predicted by chance. This is observed across large populations, not families / small groups. Mosaicism example Correct Answer: The presence of genetically distinct cell lines in the same individual. Can be somatic, resulting from an error in mitosis after fertilization that propagates in certain tissues, or can be gonadal mocaisism, in which either the sperm or egg mutates. McCune- Albright Syndrome is an example of mosaicism, but it is lethal if it occurs before fertilization. It is survivable if it is somatic. The symptoms include cafe au lait spots, polyostotic fibrous dysplasia, precocious puberty and multiple endocrine problems. Locus heterogeneity example Correct Answer: Mutations at different loci can produce the same phenotype. Albinism is an example. Allelic heterogeneity example Correct Answer: Mutations at different points within the same locus produce the same phenotype. Beta-thalassemia is an example.

Heteroplasmy example Correct Answer: Presence of both normal and mutated mtDNA results in variable expression of mitochondrial diseases. Uniparental disomy example Correct Answer: Patient inherits two copies of a chromosome from one parent. Heterozygous, or heterodisomy, indicates error in Meiosis I and homozygous, or isodisomy, indicates error in meiosis II or postzygotic duplication of one parent's chromosomes and loss of the other. **Patients who have this are exploid, because the total number of chromosomes is normal. It becomes more significant in the case of recessive diseases. What are the equations for Hardy-Weinberg, and what are the conditions of H-W equilibrium? Correct Answer: P^2 + 2pq + q^2 = 1 and p + q = 1. The conditions are: no mutation at the locus, no natural selection occurring, completely random mating and no net migration. In other words, THERE ARE NO OTHER VARIABLES AFFECTING THE LOCI IN QUESTION. In Hardy Weinberg terms, what is the frequency of an X Linked Recessive disorder in males? Females? Correct Answer: In males, it is q. In females, it is q^2. What is imprinting and what are the syndromes associated with this? Correct Answer: In imprinting, one allele is silenced by methylation. If the second is deleted / altered, it results in disease. Prader- Willi and Angelman syndrome are two diseases caused by this. Both involve deletions of active alleles on chromosome 15. Prader-Willi Syndrome Correct Answer: The maternal gene is imprinted (silenced) and the father's gene gets deleted / lost somehow, resulting in disease. **Remember, this is chromosome 15 we are talking about. The result is hyperphagia, obesity, intellectual disability, hypotonia and hypogonaism. In 25% of cases, this disease results from Uniparental Maternal Disomy. (Both copes of the chromosome come from mom and are not active). Angelman Syndrome Correct Answer: Paternal gene on chromosome 15 is imprinted, or silenced. Maternal gene is deleted or mutated. Results in inappropriate laughter (happy puppet), seizures, ataxia, and severe intellectual disability. In only 5% of cases, this is due to uniparental paternal disomy. Autosomal dominant diseases are often due to ... Correct Answer: Defects in structural genes. Autosomal Recessive diseases are often due to... Correct Answer: Enzyme deficiencies T/F. Autosomal dominant diseases are typically worse than recessive diseases Correct Answer: F. AR diseases are often more severe. What are typical characteristics of autosomal dominant diseases? Correct Answer: They are often pleiotropic-- many seemingly unrelated effects. They are also variably expressive (different from person to person). What will an autosomal recessive disorder look like on the inheritance chart? Correct Answer: You'll only see it in one generation. What are examples of X-linked Dominant diseases? Correct Answer: Hypophosphatemic Ricket (vit D resistant Rickets which results in Rickets-like symptoms and high phosphate wasting at proximal tubules), Rett syndrome, fragile X syndrome and Alport syndrome.

What do mitochondrial inheritance patterns present as? What are features of these diseases and what are examples? Correct Answer: Fathers can not transmit these. All offspring of mothers can be effected, but with variability due to heteroplasmy. Mitochondrial myopathies fall into this category of disorder-- in these diseases, patients present with MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes). These symptoms are all secondary to oxidative phosphorylation failure and muscle biopsy shows "RAGGED RED FIBERS." Achondroplasia Correct Answer: AD. FGFR3 mutation resulting in inhibited chondrocyte proliferation. MOST COMMON CAUSE OF DWARFISM. Affects limb length more than torso. FULL PENETRANCE. CHROMOSOME 4* Autosomal dominant polycystic kidney disease Correct Answer: AD. Bilateral massive enlargement of the kidneys due to cysts. 85% of cases are due to PKD1 mutations on CHROMOSOME 16. The rest are due to PKD2 on chromosome 4. Familial Adenomatous polyposis Correct Answer: AD. Adenomatous polyps covering colon with 100% progression to colon cancer. Patients must have their colon resected to survive. The polyps start after puberty. Due to defect of APC gene on chromosome 5q. Familial hypercholesterolemia Correct Answer: AD. Elevated LDL because of defective or absent LDL receptor. Results in severe atherosclerosis early in life, tendon xanthomas, corneal arcus. Hereditary hemorrhagic telangiectasia Correct Answer: AD disorder of blood vessels. AKA Osler- Weber-Rendu syndrome. findings: telangiectasias, AVMs, GI bleeding, hematuria, skin discoloration and recurrent epistaxis. Hereditary spherocytosis Correct Answer: AD. Spheroid erythrocytes due to defect in spectrin or ankyrin. Results in hemolytic anemia, high MCHC and high RDW. Also hemolytic anemia. Treatment for this is SPLENECTOMY. Huntington disease Correct Answer: AD. TRINUCLEOTIDE REPEAT DISORDER--(CAG). Chrom 4! Demonstrates anticipation. The more repeats, the lower the age of onset. Findings: depression, dementia, choreiform movements, high dopamine, low GABA, low ACh in the brain, and caudate atrophy. Li-Fraumeni Syndrome Correct Answer: AD. P53 mutation! Also known as SBLA cancer syndrome (sarcoma, breast, leukemia, adrenal). Causes multiple malignancies at early age. Marfan Correct Answer: AD. FBN1 gene mutation on chromosome 15 resulting in fibrillin defect (scaffolding for elastin.) This effects skeleton, heart and eyes. Results in long limbs, hypermobile joints, pectus excavatum, floppy mitral valve, cystic medial necrosis of the aorta and aortic aneurysms and dissection, arachnodactyly, subluxation of lenses upward and temporally. Multiple Endocrine Neoplasms (MEN) Correct Answer: AD. There are several types -- MEN I, MEN IIA, and MEN IIB. MEN 1 is caused by defect in MEN1 gene. The other two are caused by defect in RET gene. Characterized by familial tumors of endocrine glands -- pancreas, thyroid, pituitary, adrenal medulla, parathyroid.

Neurofibromatosis Type I (von Recklinghausen) Correct Answer: AD. Mutations in NF1 gene on chromosome 17. 100% penetrance with variable expression. Characterized by: LISCH NODULES (IRIS HAMARTOMAS), cafe au lait spots, pheochromocytomas, optic gliomas, cutaneous neurofibromas. Neurofibromatosis Type II Correct Answer: AD. NF2 gene on chromosome 22. Bilateral acoustic schwannomas, meningiomas, juvenile cataracts, ependymomas. Tuberous Sclerosis Correct Answer: AD. Variable expression. Numerous benign hamartomas. Effects multiple organ systems. von Hippel-Lindau Correct Answer: AD. Deletion of VHL gene on chromosome 3p. Numerous benign and malignant tumors. VHL is a tumor suppressor! Which of the mucopolysaccharidoses is NOT autosomal recessive? Correct Answer: Hunter syndrome-- XLR Which of the sphingolipidoses is NOT autosomal recessive? Correct Answer: Fabry's disease--XLR What is the genetic defect in Cystic Fibrosis? Correct Answer: CFTR defect -- chromosome 7, usually caused by deletion of Phe508. AR. MOST COMMON LETHAL GENETIC DISEASE IN CAUCASIAN POPULATION. Pathophysiology of Cystic Fibrosis Correct Answer: CFTR gene mutation causes misfolding of a ATP-gated Cl- channel that normally secretes Cl- in lungs and GI tracts and then reabsorbs Cl- in sweat. The protein never makes it to its destination. Therefore, IC Cl- becomes high, and then Na and H2O are absorbed in gut and lungs, leading to super thick mucous secretions. How is Cystic Fibrosis diagnosed? Correct Answer: High Cl- in sweat (>60mEq/L). Presents with contraction alkalosis and hypokalemia. BECAUSE OF THE LOSS OF SODIUM AND WATER IN THE ECF, THE ECF EFFECTS OF CF ARE VERY SIMILAR TO PATIENTS TAKING A LOOP DIURETIC--> K+ / H+ Wasting is concomitant with Na/H2O loss. In newborns, high immunoreactive trypsinogen is a screening tool. .Complications of Cystic Fibrosis Correct Answer: Recurrent pulmonary infections--s. aureus in infancy and p. Aeruginosa in adolescence. Chronic bronchitis and bronchiectasis --> reticulonodular pattern on CXR. Pancreatic insufficiency, steatorrhea, malabsorption of fat soluble vitamins (ADEK), biliary cirrhosis, liver disease, meconium ileus in newborns. Infertility in men because no Vas Deferens, and subfertility in women because of amenorrhea and thick cervical mucous. Nasal polyps and clubbing of fingernails. What is the treatment for Cystic Fibrosis? Correct Answer: Chest physiotherapy. Administer pancreatic enzymes. Azithromycin is used as anti-inflammatory. Albuterol. Hypertonic saline and aerosolized dornase alpha (DNAase). What is the underlying genetic condition in Duchenne Muscular Dystrophy? Correct Answer: XLR disease from frameshift or nonsense mutation in DMD gene (this is the largest protein-encoding human gene). This results in truncated dystrophin.

What protein defect is involved in Duchenne Muscular Dystrophy and what does this protein do? Correct Answer: Dystrophin helps anchor skeletal and cardiac muscle fibers -- it normally anchors the intracellular cytoskeleton (actin) to transmembrane alpha and beta dystroglycan, and this is connected to the ECM. Loss of Dystrophin results in myonecrosis, in which case high CK and Aldolase are seen. How is Duchenne Muscular Dystrophy diagnosed? Correct Answer: Western blot and muscle biopsy. What are the clinical manifestations of Duchenne Muscular Dystrophy? What is most common cause of death? Correct Answer: Inhibited muscle regeneration. Pelvic girdle muscle weakness that moves superiorly. Pseudohypertrophy of calf muscles occurs because of replacement of muscle with fibrofatty tissue. GOWER MANEUVER: patients use upper extremities to help them stand up. Waddling gait. Onset before age 5! DILATED CARDIOMYOPATHY IS MOST COMMON CAUSE OF DEATH. Becker Muscular Dystrophy: what is it caused by and what are clinical manifestations? Correct Answer: XLR. Becker Muscular Dystrophy is similar to Duchenne, except it occurs via non-frameshift insertions in the dystrophin gene, resulting in a partially functional dystrophin protein rather than a truncated protein like in Duchenne's--> therefore, clinical manifestations not nearly as severe as Duchenne's and age of onset is later (adolescence or adulthood). **Deletions can cause Becker or Duchenne MD. Myotonic Type I Muscular Dystrophy: inheritance pattern, underlying pathophys, manifestations? Correct Answer: **AD rather than XLR like Becker and Duchenne. It is caused by a CTG trinucleotide repeat in the DMPK gene--> abnormal expression of myotonin protein kinase. This results in myotonia, muscle wasting, arrhythmias, testicular atrophy, cataracts and frontal balding. Fragile X syndrome Correct Answer: X-linked dominant! Caused by a CGG trinucleotide repeat in FMR1 gene, leading to methylation and decreased expression. THIS IS SECOND MOST COMMON CAUSE OF INTELLECTUAL DISABILITY, FIRST IS DOWN SYNDROME. Causes large testes, ears, jaws, elongated faces, autism and MVP. What are the major trinucleotide repeat disorders, and what are their repeats? Correct Answer: Huntington--CAG. Fragile X--CGG. Myotonic Dystrophy--CTG. Friedrich Ataxia--GAA. (FRAGILE FRIEDRICH HUNTED MY DOG) What are the autosomal trisomies? Correct Answer: Down, Edwards, Patau. 21, 18, 13 respectively. Downs Syndrome Correct Answer: Trisomy 21. 95% of cases are due to meiotic nondisjunction, 4% due to unbalanced Robertsonian translocation between chromosome 21, 14. 1% due to mosaicism. The incidence is 1:700. 1:1500 pregnancies under age 20, 1:25 pregnancies above age 45. *This is the most common VIABLE chromosome disorder and most common cause of intellectual disability. Causes single palmar fold, gap between first and second toes, duodenal atresia, Hirschsprung's disease, heart disease (AVSD), brushfield spots. Associated with early Alzheimer's because 21 codes for amyloid precursors! Downs also causes increased risk of AML/ALL. Edwards Syndrome Correct Answer: Trisomy 18. Death usually occurs within 1 year. Occurrence is 1:8000. Signs: rocker bottom feet, severe intellectual disability, micrognathia, low set ears, prominent occiput, congenital heart disease. This is the second most common trisomy to result in a live birth.

How is Edwards diagnosed in utero? Correct Answer: PAPP-A and beta-HCG are low in first trimester. Second trimester quad screening shows low alpha-fetoprotein, low beta-HCG, low or normal inhibin A, and low estriol. BASCIALLY, LOW EVERYTHING THAT DOWNS TESTS FOR. How is Downs Syndrome diagnosed in utero? Correct Answer: In first trimester: US shows nuchal translucency and hypoplastic nasal bone, low serum PAPP-! And high free beta-HCG. Second trimester: high beta-HCG, low alpha-fetoprotein, low estriol and high inhibin A. Patau Syndrome Correct Answer: Trisomy 13. Incidence 1:15000. Findings include: severe intellectual disability, rocker bottom feet, micropthalmia, microcephaly, cleft lip / palate, holoprosencephaly, polydactyly, congenital heart disease and cutis aplasia. **Death usually within one year of birth. How is Patau syndrome diagnosed? Correct Answer: First trimester shows low free beta-HCG and low PAPP-A. Which chromosome is implicated in renal cell carcinoma? Correct Answer: 3 Which chromosome is implicated in hemochromatosis? Correct Answer: Chrom 6 Which chromosome is implicated in Williams Syndrome? Correct Answer: Chrom 7 Which chromosome implicated in Friedrich's ataxia? Correct Answer: Chromosome 9 What diseases are associated with chromosome 11? Correct Answer: Wilms tumor, beta globin gene defects (sickle cell, thalassemia) Which diseases are associated with chromosome 13? Correct Answer: Patau, Wilson, retinoblastoma (RB1), BRCA Which diseases are associated with chromosome 16? Correct Answer: ADPKD, alpha globin gene defects (thalassemia) Which diseases are associated with chromosome 17? Correct Answer: BRCA1, NF type I Which diseases are associated with chromosome type 22? Correct Answer: NF type II, DiGeorge -- 22q What is Robertsonian Translocation, what does it result in, and which chromosomes are typically involved? Correct Answer: Occurs when long arms of two Acrocentric chromosomes fuse and the short arm is lost. Balanced translocations don't result in an abnormal phenotype typically, but unbalanced translocations can result in miscarriage, trisomies, stillbirths, etc. 13,14,15,21,22 are the most commonly involved. Cri du chat syndrome: underlying causes and its manifestations? Correct Answer: It's caused by a microdeletion of the short arm of chromosome 5 (5p deleted). It results in moderate to severe intellectual disability, crying / mewing (high pitched), microcephaly, cardiac abnormalities (VSD) and epicanthal folds.

Williams Syndrome Correct Answer: Congenital microdeletion of long arm of chromosome 7 (7q deleted)--includes elastin gene! Results in elfin facies, extreme friendliness with strangers, well developed verbal skills, intellectual disability, hypercalcemia (because high sensitivity to Vit D), and heart problems. What are the 22q11 deletion syndromes? What does this deletion result in? Correct Answer: DiGeorge and Velocardiofacial syndrome. The deletion results in aberrant development of the third and fourth bronchial pouches. CATCH22---Cleft palate, Abnormal facies, Thymus aplasia, Cardiac abnormalities, hypocalcemia secondary to parathyroid aplasia. The thymic aplasia leads to T cell deficiency. What distinguishes DiGeorge from Velocardiofacial syndromes? Correct Answer: DiGeorge- thymic, parathyroid and cardiac defects. Velocardiofacial- palate, cardiac, abnormal facies Absorption of fat soluble vitamins depends on what? Correct Answer: Gut and pancreas. Remember, ADEK are the fat soluble vitamins. Which vitamin type is most toxic and why? Correct Answer: Fat soluble vitamins because they accumulate in fat cells. What types of diseases cause deficiencies in ADEK? Correct Answer: Malabsorption syndromes with steatorrhea such as Cystic fibrosis, sprue, or mineral oil intake* All water soluble vitamins wash easily out of the body EXCEPT? Correct Answer: B9 (folate) and B (cobalamin). B12 stays in the liver for 3-4 years and B9 stays in the liver for 3-4 months. B complex deficiencies result in? Correct Answer: Glossitis, dermatitis, and diarrhea. Vitamin A function / name Correct Answer: Retinol. It's an antioxidant and a constituent of visual pigments. It helps epithelial tissue differentiate into specialized epithelial tissue (pancreatic cells, mucus-secreting cells). It also helps prevent squamous metaplasia. Vitamin A deficiency Correct Answer: Nyctalopia (night blindness), Xerosis cutis (dry, scaly skin), keratomalacia (corneal degeneration), Bitot spots on conjunctiva, immunosuppression. Vitamin A excess Correct Answer: Acute toxicity: nausea, vomiting, vertigo, blurry vision. Chronic: alopecia, dry skin, liver toxicity and enlargement, arthralgias, and pseudotumor cerebri. It has TERATOGENIC effects: isotretinoin is the intense acne medication used (ACUTANE). It causes cleft lip and palate and cardiac problems. Therefore, women who use this must have a negative pregnancy test and be on two forms of bc. What is vitamin A used to treat? Where do you get it from? Correct Answer: It treats acne, wrinkles, severe cystic acne (isotretinoin), Use all-trans retinoic acid to treat acute PML. Also treats AML subtype M3. You get it from leafy vegetables and liver. What is the name and function of Vitamin B1? Correct Answer: Thiamine. In the form of Thiamine Pyrophosphate (TPP), it functions as a cofactor for several enzymes: alpha-ketoglutarate (TCA), pyruvate dehydrogenase (links glycolysis to TCA), transketolase (HMP shunt), and branched chain ketoacid dehydrogenase.

What does B1 deficiency cause? Correct Answer: ATP depletion occurs because of impaired glucose breakdown, and this build-up is worsened by glucose infusion. Aerobic tissues like brain and heart are effected first. What are the syndromes associated with B1 deficiency? Correct Answer: Wernicke-Korsakoff, Beriberi dry, beriberi wet. Wernicke: confusion, ophalmoplegia, and ataxia (CLASSICAL TRIAD), plus personality change, permanent memory loss and damage to medial dorsal nucleus of thalamus, mammillary bodies. Dry beriberi: polyneuritis, symmetrical muscle wasting. Wet beriberi: high output cardiac failure (dilated cardiomyopathy), and edema. *These syndromes are seen in alcoholics because of malnutrition and malabsorption. How is B1 deficiency diagnosed? Correct Answer: High RBC transketolase activity following B administration. Vitamin B2: name, function Correct Answer: Riboflavin. B2 is a component of flavin--FAD and FMN, and these are important in redox reactions, like the succinate dehydrogenase rxn of TCA. What does B2 deficiency cause? Correct Answer: Cheilosis around lips and mouth, corneal vascularization. Vitamin B3: name and function? Correct Answer: Niacin. constituent of NAD+ and NADP+, important for redox reactions. What is B3 derived from and what is required for its synthesis? Correct Answer: From tryptophan and B2, B6 are required for its synthesis. What does B3 treat? Correct Answer: Dyslipidemia--lowers VLDL and raises HDL. What does deficiency of B3 cause? Correct Answer: Glossitis, and severe deficiency leads to pellagra (3Ds-->dementia, diarrhea, dermatitis) + broad collar rash and hyperpigmentation of sun exposed skin. What causes B3 deficiency? Correct Answer: Hartnup disease, malignant carcinoid syndrome, and isoniazid. Carcinoid syndrome secretes serotonin and results in the high metabolism of tryptophan What is hartnup disease? Correct Answer: AR--> deficiency of neutral amino acid transporters in the renal prox tubules and on enterocytes-->neutral aminoaciduria and low abs from gut-->low tryptophan levels (because tryptophan is a neutral amino acid). This leads to pellagra-like symptoms. You treat this with a high protein diet and nicotinic acid. What does Niacin excess result in? Correct Answer: Facial flushing (included by prostaglandin not histamine and can be avoided by taking aspirin with niacin), hyperglycemia and hyperuricemia. Name of vitamin B5 and function? Correct Answer: Pantothenic acid. It's an essential component of coenzyme A, or CoA, which is a cofactor for acyl transfers. B5 is also a cofactor for fatty acid synthase. What does B5 deficiency cause? Correct Answer: Dermatitis, enteritis, alopecia, and adrenal insufficiency.

What is the name and function of vitamin B6? Correct Answer: Pyridoxine. It is converted to pyridoxyl phosphate (PLP) which is a cofactor in transamination (AST and ALT), decarboxylation rxns, glycogen phosphorylase. Synthesis of cystathionine, heme, niacin, histamine and NTs (serotonin, epi, NE, dopamine and GABA). What does B6 deficiency cause? Correct Answer: Convulsions, hyperirritability, peripheral neuropathy (deficiency inducible by isoniazid and OCPs), sideroblastic anemias due to impaired Hb synthesis and iron excess. What is the name and function of B7? Correct Answer: Biotin. Cofactor for carboxylation, which add 1 - carbon groups: pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase. What does B7 deficiency cause? What is it caused by? Correct Answer: This is very rare! It causes dermatitis, alopecia, enteritis. This can be caused by antibiotic use or excessive egg white ingestion (avidin binds biotin). What is B9 name and what is its function? Correct Answer: Folate. It is converted to THF, which is a cofactor for 1-carbon transfer / methylation reactions. *Important for synthesis of DNA and RNA. Where is B9 found? Where is it absorbed? Correct Answer: Leafy greens. Absorbed in the jejunum. There is a small reserve pool in the liver. What does B9 deficiency result in? What is it caused by? Correct Answer: Macrocytic, megaloblastic anemia; hypersegmented PMN cells, glossitis, *no neurological symptoms, unlike B12 deficiency, causes the following on lab results: high homocysteine, normal methylmalonic acid. ***This is the most common vitamin deficiency in the United States. This is seen in alcoholism and pregnancy. It can be caused by drugs: phenytoin, sulfonamides, MTX. *Supplemental folic acid in early pregnancy lowers the risk of neural tube defects. Vitamin B12 name and function Correct Answer: Cobalamin. This is a cofactor for methionine synthase (transfers methyl groups as methylcobalamin) and methylmalonyl-CoA-mutase. Methionine synthase uses B12 to synthesize methionine from homocysteine (transfers the CH3 from THF-CH3, yielding THF). Methylmalonyl-CoA-mutase turns methylmalonyl CoA into succinyl-CoA, which goes on to help synthesize heme and also goes to the TCA cycle! Where is B12 found, how is it synthesized and what causes its deficiency? Correct Answer: It is found in animal products. It can be synthesized only by certain micro organisms. Diseases of malabsorption--sprue, enteritis, D. Latum, lack of IF (pernicious anemia), gastric bypass, LACK OF TERMINAL ILEUM (from surgical resection in Crohn's disease for example), or insufficient intake. Anti-IF antibodies are diagnostic for pernicious anemia. Large amounts of B12 are stored in the liver. What does B12 deficiency result in? Correct Answer: Macrocytic, megaloblastic anemia. Hypersegmented PMNs. Build-up of methylmalonic acid and homocysteine levels in the serum, paresthesias, subacute combined degeneration (dorsal columns, lateral corticospinal tracts, spinocerebellar tracts) due to abnormal myelin With enough deficiency, permanent nerve damage can occur. What is name and function of vitamin c? Correct Answer: Ascorbic acid. It is an antioxidant and is also required for the hydroxylation of proline and lysine during collagen synthesis. It also facilitates

iron absorption by reducing it to the Fe2+ state. Also necessary for beta-hydroxylase, which converts dopamine to NE. What is vitamin C used to treat? Correct Answer: It is an ancillary treatment for methemoglobinemia, because it reduces Fe3+ to Fe2+ What are the symptoms of scurvy? Correct Answer: Swollen gums, petechiae, bruising, hemarthrosis, anemia, poor wound healing, perifollicular and subperiosteal hemorrhages, corkscrew hair, and weakened immune system. What are the symptoms of Vitamin C excess? Correct Answer: Nausea, vomiting, diarrhea, fatigue, calcium oxalate nephrolithiasis. Can increase the risk of iron toxicity in predisposed individuals (transfusions, hemochromatosis). What are the names of Vitamin D2, D3 and what are their sources? Correct Answer: D2 is ergocalciferol--it comes from plants. D3 is cholecalciferol--it comes from milk and sun exposed skin (stratum basale). What is the storage form of Vitamin D? Correct Answer: 25-OH D What is the active form of Vitamin D? Correct Answer: 1,25(OH)2-D3= calcitriol What is the function of vitamin D? Correct Answer: It facilitates absorption of calcium and phosphate in the intestine. It increases bone mineralization at low levels but increases resorption at high levels. What are the symptoms of Vitamin D deficiency? Correct Answer: It causes Rickets in kids (bone pain and deformity) and it causes osteomalacia in adults (bone pain and muscle weakness). Causes hypocalcemic tetany. Should give breastfed infants oral vitamin D* Deficiency is exacerbated by low sun exposure, pigmented skin and prematurity. What are symptoms of vitamin D excess? In what disease is excess observed? Correct Answer: Hypercalcemia, hypercalciuria, loss of appetite, stupor. This is seen in granulomatous disease (there is high activation of vitamin D by epithelioid macrophages). What is Vitamin E name and function? Correct Answer: Tocopherol / tocotrienol. It is an antioxidant -- it protects RBCs and membranes from free radical damage. **It can enhance the anticoagulation effect of warfarin! What does vitamin E deficiency result in? What does the neurological presentation look like? Correct Answer: Hemolytic anemia, acanthycytosis, muscle weakness, posterior column and spinocerebellar tract demyelination. Neurologically, it presents a lot like B12 deficiency, but no megaloblastic anemia, hypersegmented PMNs or high serum methylmalonic acid levels. Vitamin K name and function? How is it synthesized? Correct Answer: Phytomenadione, phylloquinone, phytonadione. It's made by intestinal flora. It is a cofactor for gamma-carboxylation of glutamic acid residues on blood clotting proteins * Necessary for the maturation of clotting factors II, VII, IX, X, and proteins C and S. WARFARIN IS A VITAMIN K ANTAGONIST. What does vitamin K deficiency result in? Correct Answer: Neonatal hemorrhage with high PT and high aPTT but normal bleeding time. **Neonates have sterile intestines and aren't able to synthesize

vitamin K. Vitamin K deficiency can occur after long term use of broad spectrum antibiotics. Vitamin K is not found in breast milk--neonates are given a vitamin K injection at birth to prevent hemorrhagic disease of the newborn. What is the function of zinc? Correct Answer: It's a mineral essential for the activity of 100+ enzymes. It's needed for the formation of zinc fingers (transcription factor motif). What does zinc deficiency result in? Correct Answer: Delayed wound healing, hypogonadism, low adult hair (axillary, facial, pubic), dysgeusia, anosmia, acrodermatitis enteropathica, and may predispose to alcoholic cirrhosis. What are the malnutrition syndromes and what are their manifestations? Correct Answer: Kwashiorkor and merasmus. Kwashiorkor: protein malnutrition resulting in skin lesions, edema due to low plasma oncotic pressure, liver malfunction (fatty change due to low apolipoprotein synthesis). Think small child with swollen belly Pneumonic for Kwashiorkor is MEAL (malnutrition, edema, anemia, liver - fatty). Merasmus is total calorie malnutrition resulting in muscle wasting, emaciation, with or mithout edema. Describe the process of ethanol metabolism Correct Answer: Ethanol is converted to acetaldehyde, which is then converted to acetate. Alcohol dehydrogenase converts ethanol to acetaldehyde and acetate dehydrogenase converts acetaldehyde to acetate. In both reactions NAD+ is reduced to NADH. **Peroxisomal catalase can also convert ethanol to acetaldehyde, and microsomal CYP2E can also convert ethanol to acetaldehyde using NADPH and giving off ROS. Fomepizole Correct Answer: Inhibits alcohol dehydrogenase and is an antidote for methanol or ethylene glycol poisoning. Disulfuram Correct Answer: Inhibits acetaldehyde dehydrogenase -- acetaldehyde accumulates and hangover symptoms develop. What is the limiting reagent of ethanol metabolism? Correct Answer: NAD+ What kinetics does alcohol dehydrogenase operate by? Correct Answer: Zero order kinetics What does ethanol metabolism cause in the liver? Correct Answer: High NADH / NAD+ ratio. This in turn causes: pyruvate --> lactate (lactic acidosis), oxaloacetate-->malate (this prevents gluconeogenesis and results in fasting hypoglycemia), dihydroxyacetone phosphate--> G6P (combines with FAs to make triglycerides, resulting in hepatosteatosis). The end result of all of these is the clinical picture seen in chronic alcoholism! Also, the high NADH/ NAD ratio disfavors TCA production of NADH, which means there is high utilization of Acetyl-CoA for ketogenesis resulting in keotacidosis and lipogenesis. What metabolic processes occur in the mitochondria? Correct Answer: Beta-oxidation of FAs, ketogenesis, TCA, oxidative phosphorylation, acetyl-coA production. What metabolic processes occur in the cytoplasm? Correct Answer: Glycolysis, HMP shunt, steroid synthesis (SER), protein, fatty acid, cholesterol and nucleotide synthesis. What metabolic processes occur in both cytoplasm and mitochondria? Correct Answer: Heme synthesis, urea cycle, and gluconeogenesis (HUG).

What do kinases do? Correct Answer: Transfer phosphates from a high energy molecule like ATP. What do phosphorylases do? Correct Answer: They add inorganic phosphates to substrates without using ATP. What do dehydrogenases do? Correct Answer: They catalyze oxidation - reduction reactions What do hydroxylases do? Correct Answer: They add hydroxyl groups What do carboxylases do? Correct Answer: They transfer CO2 groups with the help of biotin. What do mutases do? Correct Answer: They relocate functional groups within a molecule. What is the rate determining step of glycolysis? What are its regulators? Correct Answer: PFK-1. (+)AMP, F2,6-BP. (-)ATP, citrate RDS and regulators of gluconeogenesis? Correct Answer: Fructose 1,6 bisphosphatase. (-)AMP, F2,6-BP RDS and regulators for TCA cycle? Correct Answer: Isocitrate dehydrogenase. (+)ADP. (-)ATP, NADH RDS and regulators for glycogenesis? Correct Answer: Glycogen synthase. (+)G6P, insulin, cortisol. (-)epi, glucagon RDS and regulators for glycogenolysis? Correct Answer: Glycogen phosphorylase. (+)epi, glucagon, AMP (-)G6P, insulin, ATP RDS and regulators of HMP shunt? Correct Answer: G6PD. (+) NADP+ (-) NADPH RDS and regulators of De novo pyrimidine synthesis? Correct Answer: Carbamoyl phosphate synthetase II. (+) ATP, PRPP (-)UTP RDS and regulators of de novo purine synthesis? Correct Answer: Glutamine- phosphoribosylpyrophosphate (PRPP) amidotransferase. (-)AMP, IMP, GMP RDS and regulators for urea cycle? Correct Answer: Carbamoyl phosphate synthetase I. (+)N- acetylglutamate RDS and regulators for FA synthesis? Correct Answer: Acetyl-CoA carboxylase (ACC). (+)insulin, citrate. (-)glucagon, palmitoyl-CoA RDS and regulators for FA oxidation? Correct Answer: Carnitine acyltransferase I. (-)Malonyl CoA RDS for ketogenesis? Correct Answer: HMG-CoA synthase RDS and regulators for cholesterol synthesis? Correct Answer: HMG-CoA Reductase. (+)insulin, thyroxine. (-)glucagon and cholesterol.

What is the net ATP yield from one glucose in aerobic metabolism? Anaerobic? Correct Answer: 32 net with aerobic metabolism (via malate-aspartate shuttle) and 30 net via G3P shuttle (MUSCLE). Heart and liver use the malate aspartate shuttle . Net yield in anaerobic metabolism is 2ATP / glucose. What does arsenic do? Correct Answer: It causes glycolysis to produce zero net ATP. It inhibits lipoid acid--vomiting, rice-water stools, garlic breath. What are the activated carriers and what do they carry? Correct Answer: ATP (phosphates), NADH / NADPH / FADH2 (electrons), CoA / lipoamide (acyl groups), Biotin (CO2), THFs (1-carbon units), S- adenosylmethionone aka SAM (methyl groups), TPP (aldehydes) What are the universal electron acceptors? Correct Answer: NAD+, NADP+, FAD+ What is NAD+ usually involved in? Correct Answer: Catabolic reactions to carry reducing equivalents away as NADH What is NADPH usually involved in? Correct Answer: Anabolic reactions to deliver reducing equivalents and leave as NADP+. Steroid and FA synthesis are examples of anabolic reactions NADPH is involved in. It is also used in respiratory burst, cytochrome p450 system and glutathionine reductase. NADPH is a product of the? Correct Answer: HMP shunt What is the first step in glycolysis? What enzyme catalyzes this? Correct Answer: The first major step is the phosphorylation of glucose to yield G- 6 - P. Hexokinase and glucokinase both perform this reaction. Hexokinase Correct Answer: This enzyme phosphorylates glucose. At low glucose concentrations, hexokinase sequesters glucose in the tissues. (At high glucose conc, excess is stored in the liver). Hexokinase works in all tissues except beta cells of pancreas. It has a lower Km (which means high affinity) and a lower Vmax (lower capacity). It is NOT induced by insulin! It is feedback inhibited by G6P. Glucokinase Correct Answer: Phosphorylates glucose to make G6P in the beta cells of the pancreas and in the liver. It has a higher Km (lower affinity) but a higher Vmax (greater capacity). It IS induced by insulin, but is NOT inhibited by G6P feedback. Its gene mutation is associated with MODY-- maturity onset diabetes of the young. It is inhibited by F6P feedback** What is the net glycolysis reaction in the cytoplasm? Correct Answer: Glucose + 2Pi + 2 ADP + 2 NAD+ --> 2ATP + 2NADH + 2H20 + 2H + 2 pyruvate Which reactions in glycolysis require ATP? Correct Answer: Glucose --> G6P and F6P-->F-1,6-BP (PFK-1***RATE LIMITING STEP) Which reactions in glycolysis produce ATP? Correct Answer: 1,3-BPG <---> 3-PG (phosphoglycerate kinase) and PEP --> pyruvate (pyruvate kinase). The latter is inhibited by ATP, alanine and stimulated by F-1,6-BP

Explain how F-2,6-BP regulates glucose metabolism during fed / fasting states: Correct Answer: FBPase-2 and PFK-2 are the same enzyme but the function changes upon phosphorylation by PKA. PFK-2 is active in fed state while FBPase-2 is active in fasting state. FASTING: high glucagon--> high cAMP--> high PKA--> high FBPase-2, low PFK- 2 -->less glycolysis and more gluconeogenesis. FED STATE: insulin high --> low cAMP--> low PKA --> high PFK-2, low FBPase- 2 -->more glycolysis and less gluconeogenesis. F-2,6-BP is made from F6P and stimulates PFK-1. What is the pyruvate dehydrogenase complex and what is the reaction it catalyzes? Correct Answer: It's in the mitochondria. It links glycolysis and the TCA cycle. It's an enzyme complex. The reaction it catalyzes is: pyruvate + NAD + CoA--> acetyl CoA + CO2 + NADH. **Note, this complex is very similar to alpha-ketoglutarate dehydrogenase complex. What does the pyruvate dehydrogenase complex consist of? What are the cofactors involved? Correct Answer: "TLC For Nancy" 1. TPP (B1) 2. Lipoid acid 3. CoA (B5) 4. FAD (B2). 5. NAD (B3). What is pyruvate dehydrogenase activated by? Correct Answer: High NAD / NADH ratio, high ADP, high calcium What does pyruvate dehydrogenase complex deficiency result in? Correct Answer: This is X-Linked. It results in a pyruvate build-up. This excess then gets shunted to lactate (LDH) and alanine (ALT). Results in neurological defects and lactic acidosis, as well as high serum alanine beginning in infancy. What is the treatment for pyruvate dehydrogenase deficiency? Correct Answer: High intake of ketogenic nutrients (fat) or high leucine / lysine. LEUCINE AND LYSINE ARE THE ONLY PURELY KETOGENIC AMINO ACIDS What are the various fates of pyruvate from glycolysis? Correct Answer: 1. It can become alanine via ALT (alanine aminotransferase) (Cahill cycle). B6 is the cofactor here. Alanine carries aa groups to liver from muscle. 2. Oxaloacetate via pyruvate decarboxylase (biotin). Oxaloacetate functions in TCA cycle and also gluconeogenesis. 3. Acetyl-CoA via pyruvate dehydrogenase (B1,B2, B3,B5, lipoic acid). 4. Lactate via lactic acid dehydrogenase (B3). *This is the endpoint for anaerobic glycolysis, and is the major pathway in RBCs, WBCs, kidney medulla, lens, testes and cornea. What does the TCA cycle produce? Correct Answer: 3NADH, 1FADH2, 2CO2, 1GTP and 10 ATP per acetyl CoA (x2 per glucose molecule). What are the cofactors for alpha-ketoglutarate dehydrogenase complex? Correct Answer: Same as PDH! B1,B2,B3,B5, lipoic acid. Pneumonic "Citrate Is Krebs Starting Substrate For Making Oxaloacetate." How does ETC and oxidative phosphorylation drive ATP synthesis? Correct Answer: ETC and oxidative phosphorylation: NADH electrons from glycolysis enter the mitochondria through the malate-aspartate shuttle or the G3P shuttle. FADH2 electrons are transferred to complex II at lower energy than NADH. The passage of electrons forms a proton gradient that, coupled with oxidative phosphorylation, drives ATP production. How many ATP do one NADH yield and how many do 1 FADH2 yield? Correct Answer: 1 NADH--> 2.5 ATP. 1FADH2--> 1.5ATP.

What is another name for complex II in ETC? Correct Answer: Succinate dehydrogenase. Remember, this is where FADH2 becomes oxidized. Where exactly is ATP made? Correct Answer: By complex V in ETC, and on the mitochondrial matrix side of the inner mitochondria membrane. Rotenone Correct Answer: Inhibits complex I of ETC Antimycin A Correct Answer: Inhibits complex III Cyanide, CO Correct Answer: Inhibits complex IV Oligomycin Correct Answer: Inhibits complex V. This is an ATP synthase inhibitor** The others are called Electron transport inhibitors. What do uncoupling agents do? What are some examples? Correct Answer: They increase the permeability of the IMM, dissipating the proton gradient and leading to O2 consumption. Electron transport continues, but ATP synthesis stops. Heat is generated (is this because the energy is not being used to fuel ATP synthesis?). 2,4-DNP, aspirin, and thermogenin in brown fat are all uncouplers. 2,4-DNP is used illicitly for weight loss. Aspirin overdose results in fevers* What are the irreversible enzymes involved with gluconeogenesis? Correct Answer: "Pathway Produces Fresh Glucose". Pyruvate carboxylase, PEP carboxykinase, F-1,6-BPase, G- 6 - Phosphatase. Where is pyruvate carboxylase found? What reaction does it catalyze, what are its cofactors and what is it activated by? Correct Answer: Mitochondria. Pyruvate - > oxaloacetate (biotin, ATP needed). It's activated by acetyl-CoA. PEP carboxykinase: where is it found, which reaction, and what does it require? Correct Answer: In cytosol. Oxaloacetate-->PEP. Requires GTP. F-1,6-BPase: where is it found, which rxn, and what activates / inhibits it? Correct Answer: Cytosol. F- 1,6-BP--> F6P. (+) citrate. (-)F-2,6-BP G- 6 - Phosphatase: where is it found, what rxn? Correct Answer: In ER. G6P--> glucose. Where does gluconeogenesis occur? Where else are gluconeogenic enzymes found? Correct Answer: Mostly occurs in liver, but kidney and intestinal epithelium also have these enzymes. (T/F): muscle can participate in gluconeogenesis. Correct Answer: FALSE. Muscle does not have G- 6 - Phosphatase! What do odd chain FAs yield during metabolism? Correct Answer: 1 propionyl-CoA, and this can enter TCA cycle as succinyl CoA, undergo gluconeogenesis, and serve as glucose source. **Note, even chain FAs cannot produce glucose, as they yield only Acetyl-CoA equivalents. What is the HMP shunt producing, and for what? Correct Answer: It produces NADPH from abundant G- 6 - P. NADPH is necessary for reductive reactions (glutathione reductase in RBCs, FA and

cholesterol synthesis). This is also produces ribose, which is necessary for nucleotide synthesis and glycolytic intermediates. Where does HMP shunt occur? Correct Answer: RBCs, lactating mammillary glands, liver, adrenal cortex (site of steroid / FA synthesis). What are the 2 phases of HMP shunt? Where do these occur. Correct Answer: Oxidative (irreversible) and nonoxidative (reversible). Both occur in the cytoplasm. No ATP is used and no ATP is produced in either phase The oxidative phase: G- 6 - P dehydrogenase. G- 6 - Pi + NADP --> CO2, 2NADPH, Ribulose- 5 - Pi. Nonoxidative: Ribulose- 5 - Pi --> Ribose- 5 - Pi + glyceraldehyde- 3 - phosphate + F6P. The enzyme for the nonoxidative reaction is phosphopentose isomerase and transketolases. This rxn requires B1. What does NADPH do to the HMP shunt? Correct Answer: It inhibits G6PD. What does G6PD deficiency result in? Correct Answer: G6PD is used to keep glutathione reduced in RBCs and thereby protect them against free radical damage. If this is deficient, hemolytic anemia can occur when there are oxidative challenges (fava beans, sulfonamides, primaquine, isoniazid and other anti-tb drugs). The most common cause of hemolysis is INFECTION, because inflammatory response produces free radicals that diffuse into RBCs and cause damage. How do you get G6PD deficiency? What features are seen histologically? Correct Answer: It's X- linked recessive. More common in African Americans, as it confers malarial resistance. THIS IS THE MOST COMMON HUMAN ENZYME DEFICIENCY. Histologically, you see Bite Cells and Heinz Bodies. Bite cells result from the phagocytic removal of Heinz bodies by the splenic macrophages. Heinz bodies are denatured Hb precipitates within RBCs due to oxidative stress. What is the process of glutathione reduction in RBCs, and which enzymes are involved? Correct Answer: G6PD produces NADPH, which glutathione reductase uses to reduce GSSG--> 2 GSH. Then glutathione peroxidase uses GSH to convert H2O2 into 2 H20. Essential Fructosuria: what is the defective enzyme, what is the inheritance pattern, and what is the clinical consequence? Correct Answer: It's AR defect in fructokinase. It's a benign, asymptomatic condition because fructose does not get trapped in the cells** Fructose appears in the blood and the urine. **Galactose metabolism disorders in general are more severe than fructose metabolism disorders. Fructose intolerance: enzyme involved and clinical consequences? Correct Answer: Aldolase B. AR. F- 1 - P accumulates, resulting in a decrease in the available phosphate, which results in the inhibition of glycogenolysis and gluconeogenesis. Sx begin after pt eats juice, fruit or honey. Urine dipstick will be (-)ive, because it tests only for glucose. Sx: hypoglycemia, jaundice, cirrhosis, vomiting. What is the treatment for fructose intolerance? Correct Answer: Lower the intake of fructose and sucrose. Sucrose is glucose plus fructose! Where does fructose metabolism occur? Correct Answer: Liver Galactokinase deficiency Correct Answer: AR. Galactitol accumulates if galactose is consumed. Mild condition. Symptoms begin when infant begins breastfeeding (lactose contains galactose). Results in

galactosuria and galastosemia, infantile cataracts. May present as failure to track objects or develop a social smile. Classic galactosemia Correct Answer: AR absence of galactose- 1 - phosphate uridyltransferase. Galactitol accumulates in places including eye lens. Symptoms: failure to thrive, cataracts, intellectual disability, jaundice, hepatomegaly, can lead to E Coli sepsis in neonates** The more serious defects lead to PO4^3- depletion. What is the treatment for galastosemia? Correct Answer: Remove galactose and lactose from the diet. What is the function of sorbitol? What is the consequence of its build-up? Correct Answer: It can trap glucose in cells because glucose can be converted to sorbitol via aldose reductase. Sorbitol is then converted to fructose via sorbitol dehydrogenase. *The liver, ovaries and seminal vesicles have both of these enzymes, whereas Schwann cells, retina and kidneys have only aldose reductase and lens has mostly aldose reductase. Sorbitol, like galactitol, is osmotically active. So, in tissues that only have aldose reductase, damage can occur if sorbitol builds up--retinopathy, cataracts, peripheral neuropathy. This explains diabetic neuropathy, because hyperglycemia can lead to the trapping of sorbitol in vulnerable tissues like the eye, Schwann cells, and kidneys. What do high blood levels of galactose result in? Correct Answer: Aldose reductase also converts galactose into galactitol, which is osmotically active. High concentrations of galactose will favor this process. Lactase deficiency: cause, types, etc Correct Answer: Lactase is present on the brush border of the small intestine and it breaks down lactase into glucose and galactose. People with this deficiency are lactose intolerant. There are several types of lactase deficiency. Primary deficiency: there is an age- dependent decline in lactase due to the lack of a lactase-persistent allele. Common in Asians, Africans and Native Americans. Secondary lactase deficiency: brush border is lost due to gastroenteritis from rotavirus, AI disease. Congenital lactase deficiency: very rare. Due to a gene defect. In lactose intolerance, stool has low pH and breath has high hydrogen content with lactose hydrogen breath test. Intestinal biopsy shows normal mucosa in patients with hereditary lactase intolerance Effects of lactase deficiency? Treatment? Correct Answer: Diarrhea, cramps, bloating, flatulence. Treat by avoiding dairy or adding lactase pills to the diet. What type of amino acids are found in proteins? Correct Answer: Only L amino acids. What are the essential amino acids? Correct Answer: Glucogenic: met, Val, his. Ketogenic: Lys, leu. Glucogenic / ketogenic amino acids: Ile, phe, Thr, Trp What are the acidic amino acids? Correct Answer: Asp, Glu--> these are negatively charged at body pH Basic amino acids? Correct Answer: Arg, Lys, his. These are positively charged at body pH, except his which has no charge. ARG IS THE MOST BASIC AMINO ACID. Which amino acids are needed for long periods of growth? Correct Answer: Arg and his.