mehlman

Question 1

Student question showed DNA being replicated and they pointed to enzyme at replication fork;
what’s the enzyme?

Answer 1

helicase.

Question 2

Question asks what is acted upon by DNA ligase to form a DNA sequence that aligns complimentary
with the leading strand in DNA synthesis?

Answer 2

Okazaki fragments; the lagging strand in DNA
synthesis is composed of Okazaki fragments that are synthesized discontinuously and then
amalgamated using DNA ligase.

Question 3

82M + prostatitis + treated with pharmacologic agent for 10 days + now has sore ankle while metal
detecting; Q asks, what’s the MOA of the drug he was treated with?

Answer 3

inhibits DNA nicking;
drug is fluoroquinolone (i.e., ciprofloxacin); frequent choice for prostatitis (and pyelonephritis); MOA
is prokaryotic topoisomerase II/IV inhibitor (aka DNA gyrase); enzyme normally causes nicking in DNA
to prevent supercoiling and breakage; HY adverse effect is tendonitis (e.g., Achilles); cannot be taken
with divalent cations (i.e., foods containing calcium and iron, dec oral bioavailability of drug).

Question 4

56M + lost in forest + eats mushrooms + dies; which of the following enzymes was most likely
inhibited in this patient?

Answer 4

RNA polymerase II; a-amanitin in death cap mushrooms inhibits
RNA polymerase II (synthesizes mRNA).

Question 5

42F + has colonic polyps + tests positive for MLH1 mutation + mom has Hx of duodenal and
endometrial cancer; what’s the most likely mechanism associated with this family’s diagnosis?

Answer 5

“microsatellite instability” or “defective mismatch repair”; Dx is Lynch syndrome (hereditary
non-polyposis colorectal cancer; HNPCC); associated with mutations in mismatch repair genes MLH1,
MSH2, MSH6, PMS2.

Question 6

Researcher is investigating a DNA repair process that is characterized by the deletion of an AGTC sequence within a DNA region rich in AGTC tandem repeats; he notices this DNA repair process is inhibited when he adds DNAse to the medium; Q asks which process this is à answer = slipped strand
mispairing; student says wtf?

Answer 6

sites rich in tandem sequences (e.g., AGTC)
are prone to erroneous insertions/deletions of sequences; slipped strand mispairing can correct for
these abnormalities; DNAse disrupts process since the repair requires a transient breakage of the
phosphodiester bond, where the DNA ends are exposed and can be degraded.

Question 7

4M + congenital disorder characterized by mutation within intron sequence; which of the following
processes is most likely to be disrupted in this patient?

Answer 7

splicing; introns are sequences of
DNA that do not eventually become protein; exons are sequences that can eventually be translated to
protein; introns play a role in alternative splicing; mutations within intron sequences are known to sometimes cause problems with splicing.

Question 8

Investigator is looking at a DNA locus many hundreds of bases away from a gene that causes
upregulation of transcription of this gene; which of the following best describes this locus under
investigation?

Answer 8

answer = enhancer; enhancers are DNA loci that may be near or far from a gene and
cause upregulation of gene transcription; activators are proteins that bind to enhancers.

Question 9

Investigator is looking at prokaryotic translation process; which of the following sequences facilitates
binding of bacterial ribosome to mRNA; answer = Shine-Dalgarno sequence; student says, “Yeah I’ve
heard of that before. Wtf is that?

Answer 9

ribosomal binding site on prokaryotic mRNA; aligns start codon
on the mRNA with the ribosome to initiate translation.

Question 10

What is a chaperone protein?

Answer 10

answer = facilitates protein folding

Question 11

46M + pancreatic cancer + peripheral wasting; Q asks, which cellular organelle is most likely increased
in this patient’s muscle cells?

Answer 11

autophagic vacuoles; autophagy is a process via
which cellular components are broken down in cachexia and starvation; TNF-a is responsible for cachexia in the setting of malignancy (aka cachectic factor); wrong answers are smooth endoplasmic reticulum, rough endoplasmic reticulum, Golgi, mitochondria, and mitotic spindles.

Question 12

34F + undergoing chemotherapy; which of the following cell types in this patient is most likely to be
adversely impacted by this management?

Answer 12

answer = crypts of gut epithelium (any answer that is a
labile cell characterized by rapid turnover); crypts are site of gut stem cells.

Question 13

23M + consumes energy drink; which of the following irreversible enzymes is most likely to
demonstrate increased activity?

Answer 13

answer = pyruvate kinase (of glycolysis).
An “easy” way to remember the irreversible enzymes in glycolysis is that they are enzyme #s 1, 3, 9 – i.e., hexokinase/glucokinase (#1), PFK-1 (#3), pyruvate kinase (#9).

Question 14

21M + goes three weeks without food; breakdown of which of the following most likely explains his
ability to maintain stable blood glucose levels?

Answer 14

answer = skeletal muscle protein; glucogenic amino
acids will be liberated by muscle à converted to glucose by the liver; muscle lacks glucose-6
phosphatase so does not directly produce glucose via gluconeogenesis

Question 15

22F + goes for a run; Q asks which enzyme will most likely be activated initially by exercise in this patient

Answer 15

phosphorylase kinase, which will phosphorylate and activate glycogen phosphorylase, the main enzyme that removes glucose-1-phosphate (G1P) units from long glycogen
branches and chains. In other words, before glycogen phosphorylase can do its job, it first needs to be
phosphorylated and activated by phosphorylase kinase. After the glycogen branch has enough G1P
units removed where it is now only four G1P units in length, the first debranching enzyme 1,4
glucosidase removes three of these units, leaving only one left. The second debranching enzyme 1,6
glucosidase removes the final G1P unit.

Question 16

17F + frequent thirst and urination + markedly elevated serum glucose and ketones + serum pH of
7.1; following administration of insulin; activity of which enzyme is increased?

Answer 16

answer =
glucokinase; glucokinase is the hexokinase equivalent in the liver and is upregulated by insulin;
hexokinase is found elsewhere in the body and not upregulated by insulin; compared to hexokinase,
glucokinase has inc Km and inc Vmax, meaning that it has less affinity for glucose and greater capacity to
handle it; this makes sense, since the liver should not preferentially process glucose over other cells in
the body (e.g., muscle, brain); when serum glucose levels have risen high enough, the liver can act as
a buffer to process glucose into glycogen (glycogenesis).

Question 17

19F + eats meal; which of the following molecules is most likely to stimulate glycolysis in this patient;

Answer 17

answer = AMP; AMP + ADP stimulate glycolysis; ATP, NADH, citrate, and alanine inhibit glycolysis.

Question 18

61F + eats meal; which of the following molecules is most likely to upregulate the rate-limiting step of
glucose utilization in this patient;

Answer 18

answer = fructose-2,6-bisphosphate.

Question 19

47F + goes for a run; which of the following combinations best reflects glycogen phosphorylase in this
patient (answers are combinations of phosphorylated vs dephosphorylated, active vs inactive);

Answer 19

answer = phosphorylated + active. Glycogen phosphorylase breaks down glycogen (fasting state).
Glycogen synthase builds up glycogen (fed state). Insulin dephosphorylates. Glucagon phosphorylates.
Fed state ( insulin): enzymes dephosphorylated.
Fasting state (¯ insulin): enzymes phosphorylated.
1st step: “Are we fed or fasting?”
2nd step: “Would we expect a given enzyme to be active or inactive in this setting?”
3rd step: “Is insulin up or down?”
4th step: If insulin is up, then enzyme is dephosphorylated. If insulin is down, then enzyme is phosphorylated.

Question 20

27F + eats turkey dinner; which of the following combinations, in terms of inactive vs active,
phosphorylated vs dephosphorylated, best reflects her phosphofructosekinase-2?

Answer 20

answer = active + dephosphorylated; scenario is fed state ( inc insulin), enzyme upregulates glycolysis, so we expect it to
be active in fed state. Since insulin is up, we choose dephosphorylated.

Question 21

36F + type I diabetic + self-administers insulin; which of the following best explains the reduction of serum glucose in this patient?

Answer 21

answer = dephosphorylation of glycogen synthase; insulin
upregulates GLUT4 on adipose tissue and skeletal muscle, yes, but it also upregulates glucokinase in
the liver -> liver acts as a buffer in the setting of increased serum glucose -> glucose converted over to glycogen secondary to the dephosphorylation and activation of glycogen synthase by insulin.

Question 22

Research group is investigating a protein in RBCs that shifts the Hb-O2 dissociation curve to the right.
It is concluded that this molecule can be synthesized from a glycolytic intermediate via an RBC
enzyme called bisphosphoglycerate mutase; which of the following glycolytic substrates is most likely
the precursor to the RBC protein?

Answer 22

1,3-bisphosphoglycerate (1,3-BPG). The RBC protein is
2,3-BPG. Some 1,3-BPG from glycolysis is converted to 2,3-BPG inside the RBC via bisphosphoglycerate mutase.

Question 23

20M + low Hb + high reticulocyte count + high indirect bilirubin + high RBC 2,3-BPG; which enzyme is
deficient?

Answer 23

answer = pyruvate kinase deficiency; second most common cause of hemolysis due to
an enzyme deficiency (after G6PD deficiency); pyruvate kinase converts phosphoenol pyruvate -> pyruvate as last step of glycolysis; if decreased production of pyruvate, then decreased ATP
production -> decreased activity of Na/K-ATPase pumps on RBC -> cannot pump out sodium -> cellular swelling + lysis (hemolysis); wrong answer is glyceraldhyde-3-phosphate dehydrogenase
deficiency (would mean decreased 1,3-BPG, and ultimately decreased 2,3-BPG).

Question 24

10-month-old boy + 3rd percentile for length and weight + hypotonia + hypoglycemia + lactic acidosis
+ hyperalaninemia; Q asks which enzyme is deficient;

Answer 24

answer = pyruvate carboxylase; enzyme needed
to convert pyruvate to oxaloacetate (OAA) as an early step for gluconeogenesis (so dec glucose); if less
pyruvate is converted to OAA, then more pyruvate is shunted to alanine (pyruvate + glutamate ß<–>a-KG + alanine, via ALT and B6); more pyruvate is also converted to lactate via lactate dehydrogenase.

Question 25

Experiment performed with brown adipose tissue; discovery shows a leak of H+ ions inward across the inner mitochondrial membrane; Q asks, most likely effect on oxidative phosphorylation and energy metabolism?

Answer 25

answer = “increased ratio of oxygen consumption to ATP generated”; normally H+ in intermembrane space moves through Complex V (ATP synthase) in order to produce ATP, but if H+ leaks back across the inner membrane without going through Complex V (i.e., as a result of an upcoupling agent such as thermogenin in brown fat), more oxygen is needed to achieve the same # of ATP produced ->generates heat.

Question 26

45M + wood worker + exposed to preservative for the wood that increases heat production in his cells; which of the following mechanisms best describes this process?

Answer 26

answer = “uncoupling of oxidative phosphorylation”; 2,4-dinitrophenol is a preservative for wood that is best known for dissipating the proton gradient required for oxidative phosphorylation (electron transport chain). Uncoupling agents include 2,4-Dinitrophenol, Ethanol, Aspirin, THermogenin (DEATH). Rotenone inhibits Complex I (NADH dehydrogenase). Antimycin A inhibits Complex III. Carbon monoxide (CO) inhibits Cytochrome a3 component of Complex IV (cytochrome c oxidase).

Question 27

2M + diminished mental status + family recently moved to winter lodge with old ventilator + carboxyhemoglobin elevated; which of the following steps is inhibited in this patient?

Answer 27

Answer = G; CO inhibits Cyt a3 component of Complex IV (cytochrome c oxidase). Yes, I know. Outrageous. But it’s not our opinion that matters. It’s on a retired Step 1 NBME, so just know it.

Question 28

40M + working with paint thinner + vomiting + blurry vision + serum pH 7.27 + high-anion gap; Q asks for the pharmacologic treatment?

Answer 28

fomepizole; diagnosis is methanol toxicity; methanol is in paint thinner; Alcohol dehydrogenase converts methanol to formaldehyde, which can cause blindness and death; fomepizole inhibits this conversion by inhibiting alcohol dehydrogenase.

Question 29

Neonate + has defect in fatty acid oxidation + physical exam shows no abnormalities; Q asks, what’s the next best step in diagnosis?

Answer 29

answer = “check serum acylcarnitine concentrations”; acylcarnitines are produced during the movement of fatty acids from the cytosol to the mitochondria via the carnitine shuttle; low acylcarnitines suggests carnitine deficiency; normal acylcarnitines suggests medium- or long-chain acylCoA dehydrogenase (MCAD/LCAD) deficiency; affected children will have hypoketotic hypoglycemia (i.e., low ketones and low glucose), since ketones cannot be produced without effective beta-oxidation; ketones are produced via the assembly of acetyl-CoA units; the latter are liberated during the breakdown of fatty acids via beta-oxidation. In other words: dec beta-oxidation -> dec acetyl-CoA -> dec ketogenesis. And since acetyl-CoA is a positive allosteric regulator of pyruvate carboxylase (enzyme used in gluconeogenesis, as discussed earlier), if acetyl CoA is dec, then glucose production is dec.

Question 30

Researcher is conducting study on pyruvate carboxylase; which of the following molecules is found to increase activity of this enzyme?

Answer 30

acetyl-CoA.

Question 31

2M + hepatosplenomegaly + Hx of cardiopulmonary arrest following hypoglycemic episode + dec serum glucose + dec serum ketones + administration of medium-chain triglycerides improves his condition; diagnosis?

Answer 31

answer = long-chain acyl-CoA dehydrogenase (LCAD) deficiency; patient has hypoketotic hypoglycemia, so the answer you want to look for is either carnitine, MCAD, or LCAD deficiency; since medium-chain TGAs improved his condition, you know it can’t be MCAD deficiency (because he wouldn’t be able to process them), so LCAD deficiency is correct; for carnitine deficiency, neither medium- or long-chain TGAs would improve the condition because the carnitine shuttle would be defective (cannot move fatty acids from cytosol to mitochondria).

Question 32

3M + disorder characterized by inability of epinephrine to liberate fatty acids for energy; Q asks, which hormone is likely deficient in this patient?

Answer 32

answer = hormone-sensitive lipase (HSL); HSL is catabolic and required to move TGAs from the adipocyte into the blood; it has increased activity in the setting of higher levels of epinephrine, cortisol, and/or glucagon. In contrast, lipoprotein lipase (LPL) is anabolic and moves TGAs from the blood into the adipocyte; it has increased activity with higher levels of insulin. Other HY points: deficiency of LPL or apolipoprotein C-II causes familial hyperchylomicronemia ( inc TGAs and LDL); fibrates (e.g., fenofibrate, gemfibrozil) upregulate LPL activity and are most effective at dec serum TGAs.

Question 33

3M + acanthocytes seen on blood smear + intestinal biopsy shows large clear droplets within the enterocytes;

Answer 33

answer = abetalipoproteinemia; ¯ apolipoprotein-B48 à chylomicrons fail to exit enterocytes.

Question 34

14F + LDL of 280 mg/dL + father died of MI in his early-40s; what’s the mechanism for this patient’s condition?

Answer 34

answer = deficiency of LDL receptor; Dx is familial hypercholesterolemia

Question 35

Investigator is studying vancomycin-resistant bacterial strain; after many generations of propagation, vancomycin-sensitivity is observed at a frequency of one per 200 cells; what’s the mechanism for loss of resistance?

Answer 35

answer = “plasmid loss”; most antibiotics resistance genes are located on the bacterial plasmid.

Question 36

Researcher develops toxin that causes inhibition of GTPase activity of G-alpha-s G proteins; which would most likely increase in a cell as a result of this toxin?

Answer 36

answer = cAMP; GTPases normally function to shut off G-protein function; if GTPase activity is impaired (e.g., in cancer), there is constitutive (continual; increased) activity of the G-protein.

Question 37

Agonism of G-alpha-q G proteins

Answer 37

increases phospholipase C, inositol 1,4,5-triphosphate (IP3), and diacylglycerol

Question 38

Agonism of G-alpha-I

Answer 38

inhibits adenylyl cyclase -> decreases cAMP.

Question 39

Agonism of G-alpha-s

Answer 39

activates adenylyl cyclase -> increases cAMP.

Question 40

Receptors for G-alpha-q

Answer 40

HAVe 1 or 3 M&Ms -> Histamine 1, Alpha 1, Vasopressin 1, Muscarinic 1, Muscarinic 3.

Question 41

Receptors for G-alpha-i

Answer 41

MAD2s -> Muscarinic 2, Alpha 2, Dopamine 2.

Question 42

Receptors for G-alpha-s

Answer 42

Beta 1, Beta 2, Dopamine 1, Histamine 2, Vasopressin 2 (essentially memorize both aforementioned mnemonics, and then the receptors that don’t fit into either you know are G-alpha-s).

Question 43

Researcher studying influenza virus and antigenic shift; which of the following mechanisms best explains this process?

Answer 43

answer = “reassortment”; antigenic shift -> pandemics -> reassortment of viral segments; antigenic drift -> epidemics -> point mutations in hemagglutinin and/or neuraminidase.

Question 44

13M + yellow eyes following treatment for infection + blood smear shows precipitated hemoglobin within RBCs; what’s the most likely mechanism for this condition?

Answer 44

“increased RBC membrane oxidation”; Dx is glucose-6-phosphate dehydrogenase (G6PD) deficiency; X-linked recessive; due to deficient NADPH production via the HMP shunt; NADPH is a reducing agent that dec oxidation of RBC membranes; patients have inc hemolysis with certain drugs (i.e., sulfa, dapsone, hydroxychloroquine), infections, and, famously, fava beans. Blood smear shows degmacytes (bite cells) and Heinz bodies (precipitated, oxidized hemoglobin).

Question 45

19F + enzyme deficiency + increased indirect bilirubin; which enzyme is most likely deficient in this patient?

Answer 45

answer = pyruvate kinase deficiency -> RBC cannot make sufficient ATP to drive Na out of the cell -> water stays with sodium -> RBC swelling -> lysis; second most common cause of hemolysis due to an enzyme deficiency (after G6PD deficiency); pyruvate kinase deficiency is AR so can occur in females; G6PD (XR) only presents in males.

Question 46

12M + Hx of recurrent Staph infections + dihydrorhodamine test confirms diagnosis; the deficient enzyme in this patient acts on which of the following as a substrate?

Answer 46

answer = molecular oxygen; diagnosis is NADPH oxidase deficiency (chronic granulomatous disease); nitroblue tetrazolium assay now obsolete and is the wrong answer on one of the Step 1 NBMEs (dihydrorhodamine test being correct); NADPH oxidase required as initial enzyme in order to ultimately generate sufficient H2O2 to overwhelm catalase (+) organisms; even though the latter generate catalase, which breaks down H2O2, healthy individuals produce enough H2O2 via respiratory burst pathway to outpower these pathogens. Molecular oxygen (O2) is the substrate of NADPH oxidase; should be noted that myeloperoxidase deficiency leading to insufficient generation of halide-hydroxyl radicals (bleach; hypochlorous acid) is equally HY on NBME yet underemphasized in other resources. NADPH is a reducing agent used in a variety of reactions produced via the G6PD pathway (HMP shunt).

Question 47

6-month-old boy + enlarged tongue + hypotonia + cardiomegaly + muscle biopsy shows increased glycogen; Q asks which enzyme is deficient

Answer 47

answer = alpha-1-4-glucosidase (aka lysosomal acid maltase); diagnosis is Pompe syndrome (glycogen storage disease type II).

Question 48

4-month-old boy + 2-month Hx of frequent crying and tremulousness presenting a few hours after feeds + massive hepatomegaly + hypoglycemia + lactic acidosis; which enzyme is deficient?

Answer 48

answer = glucose-6-phosphatase; Dx is von Gierke (glycogen storage disease type I); classically presents as young child with hepato-/hepatosplenomegaly, lactic acidosis, and hypoglycemia.

Question 49

4M + coarse facial features + contractures of large joints + markedly elevated plasma lysosomal enzyme levels; Q asks, what’s the most likely mechanism for this condition?

Answer 49

answer = “abnormal targeting of enzymes to lysosomes”; diagnosis is I-cell disease; as discussed, mechanism is inability of the Golgi to make mannose-6-phosphate, which is required for proper targeting of lysosomal hydrolases to the lysosomes for storage; if they can’t go to the lysosomes, they are secreted into the plasma.

Question 50

Researcher is investigating the primary structure of a molecule that is defective in osteogenesis imperfecta; which amino acid is likely to be most abundant in this molecule?

Answer 50

answer = glycine; primary structure of collagen is Gly-X-Y, where glycine composes one-third of collagen; X and Y are usually proline or lysine, which are then frequently hydroxylated to become hydroxyproline and hydroxylysine.

Question 51

12F + tall and lanky + myopia on school visual acuity exam + thrombotic episode; Dx?

Answer 51

answer = homocystinuria (AR); usually due to deficiency of cystathionine synthase; homocystine = two homocysteines bound together; Q will be Marfanoid body habitus in school-age kid with thrombotic episode +/- a lens dislocation; B6 can be used as Tx in some patients.

Question 52

13M + seizure + lens dislocation two years ago + serum cystathionine is decreased; what is most likely to be increased in this patient?

Answer 52

answer = methionine; shunting of homocysteine to methionine in this case.

Question 53

31M + tall + flat feet + pectus excavatum + mid-systolic click; the abnormal molecule in this patient is best described as which of the following

Answer 53

answer = “glycoprotein that forms a sheath around elastin” (fibrillin); Dx is Marfan syndrome; AD; FBN1/2 genes on chromosome 15; fibrillin is not related to collagen (it stabilizes elastin); tall, lanky stature; mitral valve prolapse + aortic regurg (myxomatous degeneration) + aortic dissection (cystic medial necrosis) can be seen; scoliosis; arachnodactyly (long fingers); pes planus (flat feet); chest wall abnormalities (pectus excavatum/carinatum; abnormal hair distribution).

Question 54

28M + tall + flat feet + mitral valve prolapse + headaches;

Answer 54

answer = MEN 2B, not Marfan syndrome.

Question 55

3M + atrial myxoma + hyperpigmentation around the lips + hyperthyroidism; what’s the most likely diagnosis?

Answer 55

answer = Carney complex.

Question 56

Researcher is looking at a compound that is taken up by cells + no energy is required for uptake + the compound is not concentrated in the cell; Q asks, which mechanism best describes this mechanism of transport?

Answer 56

carrier-mediated diffusion (facilitated diffusion/transport).

Question 57

35F + recurrent bronchitis and sinusitis throughout life + Hx of ectopic pregnancy + cardiac exam shows point of maximal impulse at the 4th intercostal space right midclavicular line + biopsy of nasal polyp taken; Q asks, which structure is most likely to be absent on electron microscopy of the biopsy specimen?

Answer 57

dynein arms; Dx is primary ciliary dyskinesia (Kartagener syndrome); dynein arms are required for function of cilia, which normally line the pseudostratified columnar epithelium of the respiratory tree à decreased function of cilia à increased respiratory tract infections; Kartagener is associated with situs inversus / dextrocardia; ectopic pregnancies in females (cilia normally line Fallopian tubes) and ¯ sperm motility in males (infertility); a cilium comprises a 9x2 circumferential pattern of microtubules on 2D-cross-section (i.e., a cilium is much larger than microtubules); should be noted that whilst sperm demonstrate ¯ motility in Kartagener, there are absent sperm in cystic fibrosis due to CBAVD (congenital bilateral absence of vas deferens) – i.e., recurrent sinopulmonary infections + absent sperm = CF; whereas recurrent sinopulmonary infections + immotile sperm = Kartagener. Cross-section of cilium showing 9x2 microtubules circumferentially:

Question 58

6M + 3rd percentile for weight and height + failed to pass meconium at birth; which of the following molecular combinations best describes the defective channel inherent to this patient’ disease?

Answer 58

cAMP and ATP; diagnosis is cystic fibrosis (AR; chromosome 7); CFTR is a cAMP-mediated, ATP-gated chloride channel; the defective channel is retained within the RER of the cytosol (i.e., it is not found on the cell membrane); sweat chloride test demonstrating >60 mEq/L is more accurate than genotyping due to increased allelic heterogeneity (i.e., many diseased alleles can produce the CF phenotype; even detailed genetic screening panels only detect upward of 90-96% of the most common mutations); DF508 (deletion of phenylalanine at position 508) is most common CF mutation; patients have negative nasal transepithelial potential difference (one type of diagnostic test); Staph aureus exceeds Pseudomonas for most common cause of CF pneumonia in first decade of life; after first decade, Pseudomonas exceeds Staph; phenotypically normal sibling of patient with CF has 2/3 chance of being a carrier (i.e., we can eliminate the aa on the Punnett square because the unaffected sibling clearly doesn’t have the disease, so 2Aa / 2Aa + 1AA); dornase-alfa (correct, not alpha) is a nucleotidase that can help clear mucous from respiratory tree; N-acetylcysteine has -SH groups that can help breakdown mucous; guaifenesin softens mucous; ivacaftor is CFTR modulator that can help re-fold protein into functional form.

Question 59

24F + autosomal recessive condition + low serum vitamin D + Hx of two episodes of Pseudomonas pneumonia; what is most likely to occur on a cellular level in this patient’s pancreatic ducts?

Answer 59

“upregulation of ENaC”; Dx is cystic fibrosis; CFTR channel is defective -> Cl- cannot be secreted out of pancreatic ducts into the lumen à more Cl- is retained in the cell -> more Na+ moves from lumen into the cell to balance charge via ENaC -> water follows Na+ -> secretions within pancreatic duct lumen inspissate (i.e., desiccate within a lumen) -> exocrine pancreas malsecretion -> impaired absorption of fat-soluble vitamins and macronutrients -> failure to thrive.

Question 60

17F + taking OCPs + taking isotretinoin for acne past two years + has headache + is vegan; which vitamin is most likely responsible for her headache

Answer 60

vitamin A -> isotretinoin (high-dose vitamin A) and OCPs both can cause pseudotumor cerebri (increased intracranial pressure); veganism can cause B12 deficiency, not excess, nor does that relate to headaches.

Question 61

Investigator is looking at enzyme that is a giant complex; which of the following is most likely?

Answer 61

answer = pyruvate dehydrogenase (converts pyruvate -> acetyl-CoA of TCA cycle); described as giant complex of vitamins B1, B2, B3, B5, and lipoic acid.

Question 62

42M + alcoholic + high MCV; Q asks, which combination of serum methylmalonic acid and homocysteine is most likely in this patient?

Answer 62

normal methylmalonic acid (or methylmalonyl-CoA), homocysteine; diagnosis is folate (B9) deficiency. Learning point is: o B9 deficiency: normal methylmalonic acid (or methylmalonyl-CoA), homocysteine. o B12 deficiency: methylmalonic acid (or methylmalonyl-CoA), homocysteine. o This is because without B9 and B12, there is less homocysteine à methionine. o However B12 alone is needed to convert methylmalonyl-CoA into succinyl-CoA.

Question 63

Experiment performed showing HPV16 E6 protein causes p53 protein degradation; Q asks, which cellular enzyme will target p53 as a result of this viral protein

Answer 63

ubiquitin ligase; ubiquitination will target proteins for degradation by the proteasome.

Question 64

31F + Pap smear shows atypical squamous cells + molecular diagnostic studies show viral E6 protein; Q asks, this protein promotes cell growth and malignancy via what mechanism?

Answer 64

answer = “degradation of p53”; HPV16 E6 protein targets p53; HPV18 E7 protein targets RB; both are tumor suppressor proteins; you can remember this because 16 comes before 18, as 6 comes before 7, as P comes before R.

Question 65

62M + back pain + restrictive cardiomyopathy + renal failure + biopsy of kidney shows a birefringent pattern with Congo red stain; Q asks, what is the structure of the material that is stained?

Answer 65

answer = b-pleated sheet; diagnosis is multiple myeloma causing cardiac and renal amyloidosis; amyloid stains apple green birefringent with Congo red stain because of its b-pleated sheet structure.

Question 66

Neonate + several fractures occurred during birth + shortened extremities + misshapen long bones + poor skull mineralization; Q asks, this girl has a defect in which of the following?

Answer 66

answer = collagen; diagnosis is osteogenesis imperfecta (collagen I).

Question 67

Experiment with fish embryos; two pronuclei used to make embryo; results of study show that if both pronuclei are of maternal or paternal origin, the embryo fails to develop properly; why?

Answer 67

imprinting; normally two alleles are inherited for each gene an organism has (one from each parent), but various alleles will sometimes be silenced from one parent and expressed in the other; if the allele coming from mom is silenced, that’s called maternal imprinting; if the allele coming from dad is silenced, that’s called paternal imprinting. o Prader-Willi syndrome (PWS; many involved genes; mental retardation + hyperphagia) is classic maternal imprinting -> gene coming from mom is normally silenced; dad’s gene is supposed to be expressed but is deleted or mutated (“Willi hates his dad” because dad’s gene is deleted); even if mom’s gene is healthy, since it is normally silenced, it will not be expressed. o Angelman syndrome (AS; UBE3A gene on chromosome 15; “happy puppet”) is classic paternal imprinting -> gene coming from dad is normally silenced; mom’s gene is supposed to be expressed but is deleted or mutated (“Mom is not an angel” because mom’s gene is deleted); even if dad’s gene is healthy, since it is normally silenced, it will not be expressed. o PWS and AS can also be caused by uniparental disomy, where both alleles are erroneously inherited from the same imprinted parent. § For PWS (maternal uniparental disomy), since the gene is normally maternally imprinted, if both alleles are inherited from mom, both will be silenced; disease occurs because there’s no paternal allele available to be expressed. § For AS (paternal uniparental disomy), since the gene is normally paternally imprinted, if both alleles are inherited from dad, both will be silenced; disease occurs because there’s no maternal allele available to be expressed.

Question 68

23M + develops pancreatic cancer + mom had colon cancer + uncle had liver cancer; investigative studies show mutation in TP53 gene; Q asks, which process accounts for difference in presentation among family members;

Answer 68

pleiotropy; diagnosis is Li-Fraumeni syndrome (TP53 gene mutation results in p53 protein abnormality).

Question 69

40M + pancreatic cancer due to Li-Fraumeni syndrome; Q asks, what mechanism is responsible for development of cancer in this patient?

Answer 69

“loss of heterozygosity”; patient was born with one diseased allele in every cell (i.e., one hit); after spontaneous mutation in second allele, disease occurred. The p53 protein is a tumor suppressor that halts the cell cycle in the setting of DNA damage; sometimes the Q will simply have “failure of DNA repair” as the answer for Li-Fraumeni.

Question 70

44M + cognitive decline over the past six months + abnormal movement of limbs + father had similar presentation in his 50s; Q asks, what mechanism best explains this patient’s presentation?

Answer 70

answer = anticipation; Dx is Huntington disease (AD, chromosome 4), which is caused by 40+ trinucleotide repeats (TNR) of CAG codon; anticipation is a HY term associated with TNR disorders that refers to the disease presenting increasingly more severe, and earlier, with each successive generation. This is due to expansion of the number of TNR with each generation.

Question 71

34F + tonic-clonic seizure + tingling of hands and feet + involuntary contraction of muscles of hands + hyperreflexia; Q asks which electrolyte is most likely abnormal?

Answer 71

calcium (hypocalcemia); leads to hyperreflexia and tetany.

Question 72

71M + has an MI + revascularization is achieved via percutaneous coronary intervention + serum troponin + CK-MB increase following the procedure; Q asks why?

Answer 72

answer = “membrane lipid peroxidation”; reperfusion injury occurs due to oxygen radicalsfollowing coronary revascularization

Question 73

15M + intermittent orthostatic hypotension + low serum norepinephrine concentration + high serum dopamine concentration; which enzyme is deficient?

Answer 73

dopamine b-hydroxylase

Question 74

1M + increased serum phenylalanine; Q asks what is deficient in this patient (answers are all substrates and cofactors rather than enzymes)

Answer 74

tetrahydrobiopterin (BH4, THB), which is a cofactor for phenylalanine hydroxylase; Dx is malignant PKU, which is PKU due to BH4 deficiency rather than phenylalanine hydroxylase deficiency.

Question 74

6-month-old boy + musty/mousy body odor + fairer skinned compared to siblings + slow mental progression; Q asks, this condition could have been prevented how?

Answer 74

“routine newborn screening”; Dx is phenylketonuria (PKU); picked up on heel-prick test at birth; deficiency of phenylalanine hydroxylase (cannot convert phenylalanine -> tyrosine); results in mental retardation; newborn screening test must be more sensitive to best pick it up; Tx = avoid phenylalanine in diet.

Question 75

18M + goes for long run + depletes glucose stores; Q asks, which organ, in addition to the liver, will release newly produced glucose in the patient

Answer 75

kidney; the kidney and liver are both able to carry out gluconeogenesis. Skeletal muscle notably cannot produce glucose because it lacks glucose-6-phosphatase.

Question 76

20M + 6-year-Hx of seizure disorder + flesh-colored papules on bridge of nose and in the nasolabial folds; diagnosis?

Answer 76

tuberous sclerosis (TSC); AD; chromosomes 9 and 16 (hamartin and tuberin proteins); subependymal or periventricular nodules seen on MRI; hypopigmented macules (ash leaf spots); hyperpigmented velvety lesions (shagreen patches); cardiac rhabdomyoma; renal angiomyolipoma; subungual fibromas (nailbed tumors); vignette will also give a young child who has writhing movements in his/her sleep to suggest seizures.

Question 77

Experiment is performed showing a nutrient causes increased gene products detectable by Western blotting + no change in gene products detected by Northern blotting or PCR; Q asks, what does the nutrient cause intracellularly?

Answer 77

answer = “translation of mRNA”; Western blot detects protein; Northern blot detects RNA; Southern blot detects DNA; PCR detects DNA. Transcription is the process of DNA -> RNA; translation is the process of RNA -> protein.

Question 78

Experiment is performed visualizing changes to RNA via electron microscopy; Q asks which change occurs in the cytosol?

Answer 78

“association with P-bodies”; DNA is transcribed to hnRNA (heteronuclear RNA); hnRNA then undergoes three main changes in the nucleus: 1) addition of poly-A tail to 3’ end, 2) addition of 7-methylguanosine cap to 5’ end, and 3) splicing out of introns; after these three changes are made in the nucleus, the hnRNA is now called mRNA (messenger RNA). The mRNA then leaves the nucleus for the cytoplasm, where it associates with P-bodies, which are “docking centers” for mRNA to be sequestered and translated at a later point in time.

Question 79

28F + experiences spontaneous abortion; Q asks, what’s the most likely mechanism for this?

Answer 79

“unbalanced chromosomal rearrangement,” which is the most common cause of spontaneous abortion.

Question 80

Investigator looking at cellular effects of increased serum insulin; which of the following combinations of findings is most likely;

Answer 80

inc nuclear/cytoplasmic shuttling; inc serine phosphorylation; dec ubiquitination; insulin activates MAP tyrosine kinase and serine/threonine pathways, which will cause inc nuclear/cytoplasmic shuttling and inc serine phosphorylation; ubiquitination is dec because this is a catabolic process but insulin is anabolic.

Question 81

20M + weakness + twitching + muscle biopsy shows ragged red fibers; Q asks which cellular organelle on the following diagram is fucked up.

Answer 81

mitochondrion; “ragged red fibers” is buzzy description seen in myoclonic epilepsy with ragged red fibers (MERRF syndrome).

Question 82

4M + Hx of recurrent ear infections + hepatosplenomegaly + studies show deficient N acetylglucosamine-1-phosphotransferase + analysis of skin fibroblasts shows they secrete large amounts of acid hydrolase into the culture medium; Q asks, these hydrolase enzymes are unable to target to which organelle?

Answer 82

lysosome; diagnosis is I-cell disease; deficient enzyme leads to inability to produce mannose-6-phosphate, which normally enables hydrolases at the Golgi to be targeted to the lysosomes; if the Q asks for the location of the deficient enzyme, choose Golgi; if the Q asks for the location the hydrolases cannot be targeted to, choose lysosomes. Presentation is normally restricted joint movement + coarse facial features, but can also present as recurrent ear infections and hepatosplenomegaly.

Question 83

3M + developmental delay + ophthalmoplegia + hypotonia + hearing loss in mother + uncle had stroke-like episodes in his 20s; Q asks, which mechanism explains the findings in this family?

Answer 83

heteroplasmy; diagnosis is a mitochondrial disorder (in this case, MELAS, which is Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes); you don’t need to know MELAS specifically, but just know ear and/or eye problems, lactic acidosis, and hypotonia suggest mitochondrial disorders in general; mitochondrial disorders are always maternally inherited (i.e., only females pass on to offspring); heteroplasmy is variation of mitochondrial disease severity based on the proportion of diseased mitochondrial DNA (not chromosomal DNA) inherited; each oocyte from the mom will have hundreds to thousands of copies of mitochondrial DNA with differing proportions of diseased vs healthy copies, leading to offspring with varying disease severity. Heteroplasmy is specifically applied to this process for mitochondrial diseases; in contrast, variable expressivity is applied to disorders with complete penetrance that are not mitochondrial (e.g., NF1).

Question 84

Neonate + marked hypopigmentation + blue irides; Q asks, this condition is caused by a defective enzyme located in which organelle?

Answer 84

melanosome; diagnosis is albinism, which is usually caused by deficient/defective tyrosinase, a melanosomal enzyme.

Question 85

27M + severe muscle cramping with exercise + venous blood sampling shows post-exercise lactic acid does not increase compared to pre-exercise levels; Q asks, which enzyme is most likely deficient?

Answer 85

muscle glycogen phosphorylase; diagnosis is McArdle syndrome (glycogen storage disease type V).

Question 86

16F + gives birth to neonate with epicanthal folds, slanted palpebral fissures, single palmar crease, and low IQ; karyotyping of the neonate shows abnormality in 100% of cells; what’s the most likely mechanism for her child’s condition?

Answer 86

Robertsonian translocation; child has Down syndrome (trisomy 21) due to inheriting the long arm of chromosome 21 attached to chromosome 14 of one of the parents tri-screen in first trimester of pregnancy at 8-10 weeks shows dec PAPP-A, inc b-hCG, incnuchal translucency; ultrasound shows hypoplastic nasal bone (flattened facies); quad screen in second trimester of pregnancy at 16-20 weeks shows dec AFP, inc b-hCG, dec estriol, inc inhibin-A the variables that have an “H” in them are the ones that have increase arrows

Question 87

Neonate born with microcephaly + prominent occiput + clenched hands + low-set ears; what chromosomal abnormality is most likely to be seen?

Answer 87

trisomy of chromosome 18; diagnosis is Edward syndrome; presentation is microcephaly + prominent occiput + clenched hands + low-set ears; flattened facies not characteristic (that’s Down due to hypoplastic nasal bone); second trimester quad screen shows dec for all four variables: AFP, b-hCG, estriol, inhibin-A.