PBL Cases 1-8

Question 1

What is the inheritance pattern of cystic fibrosis?

Answer 1

autosomal recessive

Question 2

What chromosome is the CFTR gene located on?

What is the most common mutation and what does it lead to?

Answer 2

• Genetic Mutation: CFTR gene located at chromosome 7
  
  • Most Common Mutation: delF508, which is deletion of phenylalanine at 508-position
  • Leads to misfolding and degradation

Question 3

What is the epidemiology of cystic fibrosis?

• Which two populations have the highest incidence?
• What disease is present in high incidence populations?

Answer 3

• Epidemiology: Ashkenazi Jewish has highest (1/24), followed by Whites.
  
  • High presence of cholera in high incidence populations. With half functional CFTR you do not die from dehydration when infected with cholera because of the ability to retain more chloride ions & therefore water than those who are not carriers.

Question 4

What are the limitations of genetic screening exams?

Answer 4

• Limitations of Genetic Screening Tests for CF: multiple mutations, all of which are not deleterious

Question 5

What does the CFTR gene encode for?

What is the role of the CFTR protein in epithelial cells?

Answer 5

• CFTR is a chloride channel located on the apical membrane of epithelial cells of different organ systems
• Mucous lubricates lining of airways, digestive system, reproductive tract, etc.

Question 6

How does a normal CFTR protein function biochemically?

Answer 6

• Normal CFTR: increases the secretion of chloride ion via active transport and reduces the passive reabsorption of sodium ions “via regulation of epithelial Na channel”
  
  • CFTR has direct inhibition of the Na channel → with chloride efflux, Cl- ions negatively inhibits sodium influx

Question 7

How does a mutated CFTR protein function biochemically at the membrane?

Answer 7

• Mutated CFTR: decreases the secretion of chloride ion and augments the reabsorption of sodium ion (with passive water reabsorption)
  
  • Hyperconcentrated, “dehydrated” mucous

Question 8

How do defects in CFTR proteins translate to dysfunction in sweat glands?

Answer 8

• CFTR actively transports chloride ions out of sweat gland lumen into surrounding tissue
• In sweat, sodium follows chloride ions out of the sweat gland lumen
• Improper CFTR leads to increased NaCl released out of sweat gland lumen onto skin

Question 9

How do defects in CFTR proteins translate to dysfunction in intestines/pancreas/lungs?

Answer 9

• Mutated CFTR channels → chloride is not actively transported into the lumen → ENaC (sodium channel) is not negatively inhibited → increased sodium reabsorption → increased water reabsorption → dehydrated mucous layer of lumen (muconeum ileus – obstruction of small intestines in neonates)

Question 10

How does the sweat chloride test determine the presence of cystic fibrosis?

Answer 10

• Cl- conductance is virtually abolished because CFTR is the only outlet for chloride.
• When Na+ attempts to flow out of a CF duct through remaining sodium-selective pathways, it is unaccompanied by Cl- and so it creates an excess of negative charge in the duct that attracts Na+ and prevents its further absorption.
• The net result is that very little NaCl is reabsorbed, resulting in a high salt content in CF sweat.

Question 11

What defects and symptoms occur in the respiratory tract due to CFTR dysfunction?

Answer 11

• thick and sticky mucous (assoc. with CF) clogs the tubes that moves air in and out of your lungs
  
  • Symptoms: wheezing, breathlessness, lung infections

Question 12

What defects and symptoms occur in the pancreas due to CFTR dysfunction?

Answer 12

• Pancreatic Insufficiency: The thick mucus can also block tubes that carry digestive enzymes from your pancreas to your small intestine. Without these digestive enzymes, your intestines aren’t able to completely absorb the nutrients in the food you eat.
  
  • Symptoms: failure to thrive, CFRD (CF related diabetes)

Question 13

What are three multi-organ system based treatments for cystic fibrosis?

Answer 13

• Enzymes to allow for digestion of food
• Shaking Vest to breakup mucous in lungs for easier breathing
• Antibiotics to fight off infections caused by ineffective mucous

Question 14

What defects and symptoms occur in the reproductive system due to CFTR dysfunction?

Answer 14

• Reproductive System: vas deferens and fallopian tubes filled with thick mucous

Question 15

What are the six classes of CFTR mutations, their functional consequences, and their treatments?

Answer 15

Question 16

What is the inheritance pattern of G6PD deficiency and what are some causes of genetic selectivity?

Answer 16

• Inheritance pattern: X-linked recessive
  
  • Males are hemizygous – one mutant gene leads to full blown deficiency
  • Females are mosaic – x-link deactivation leads to differing levels of deficiency
• Causes of Genetic Selectivity: Carriers offer resistance to a deadly form of malaria called plasmodium falciparum
  
  • Falciparum targets mature red blood cells

Question 17

What are some of the most common mutations associated with G6PD deficiency that may alter protein structure/enzyme activity?

Answer 17

• Missense point mutations (change in one nucleotide that could alter AA) at Xq48
• Most abnormal alleles result in a functionally normal enzyme but have a shortened life span within the red cell

Question 18

What is the role of G6PD in the hexose monophosphate shunt pathway and how can oxidative stress tip the balance of NADP-NADPH in the erythrocyte?

Answer 18

• G6PD oxidizes G6P while reducing NADP+ to NADPH
• NADPH can then reduce oxidized glutathione, in order to reduce H2O2
• G6PD is involved in the only pathway in RBCs that can reduce oxidants

Question 19

In the G6PD case, oxidative stress was caused by…

Answer 19

Oxidative stress is caused by…

• Fava beans
• Bactrim (has a FR, which oxidizes GSH back to GSSG)
• Severe infections

Question 20

What are the consequences of oxidative stress (think the G6PD case)?

Answer 20

• Oxidizes Fe²⁺ to Fe³⁺, changing hemoglobin to methemoglobin, which cannot bind O₂
• Denatures cytosolic and membrane proteins → hemolysis → heme breakdown → bilirubin (toxic) → juandice
• Denatured hemoglobin → Heinz’s bodies → Bite cells after macrophages eat Heinz’s bodies

Question 21

Explain how the imbalance between NADP-NADPH causes hemolysis. How does jaudice come from this?

Answer 21

• Decreased [NADPH] → decreased [GSH] → increased [ROS] → oxidation of Fe²⁺ to Fe³⁺ → hemoglobin converted to methemoglobin → increased [ROS] denatures cytosolic and membrane proteins → hemolysis → hemoglobin breakdown → heme exposed → porphorin ring exposed → formation of bilirubin (toxic) → increased blood [bilirubin] → juandice

Question 22

What is the structure of hemoglobin and some characteristics?

Answer 22

• Hemoglobin
  
  • Tetramer – each monomer is called globin
  • Each monomer has a heme center that holds Fe²⁺ that binds an O₂ molecule to transport to tissues
  • Cooperative binding – when one O₂ binds to one globin, binding affinity increases for other globins

Question 23

What is the interrelation of Fe²⁺ and Fe³⁺?

Answer 23

• Interrelation of Fe²⁺ and Fe³⁺
  
  • Fe²⁺ is oxidized to Fe³⁺ → hemoglobin is converted to methemoglobin → can no longer bind oxygen

Question 24

What are the two routes that convert methemoglobin to hemoglobin?

Answer 24

• Two Routes of Converting Methemoglobin to Hemoglobin
  
  • Cytochrome b5 Reductase: uses NADH produced from glycolysis
  • Methemoglobin Reductase: converts methylene blue to leukomethylene blue using NADPH → leukomethylene blue reduces Fe3+ back to Fe2+

Question 25

Relate the concepts of oxygen saturation, partial pressure of oxygen and the hemoglobin-oxygen dissociation curve. * What factors affect the oxygen binding cuve and how does it move?

Answer 25

Question 26

Describe four factors that can acutely change in a patient that will alter a drug’s volume of distribution and clearance.

Answer 26

* Dehydration – affects filtration rate of blood → less drug is filtered out * The metabolism rates * Children have an increase in metabolism, resulting in higher drug metabolism * The elderly are affected due to diminished cellular function, receptor function and drug elimination difficulty. * Renal Function affects the drug clearance and reabsorption. * Liver diseases affect the biotransformations and absorption.

Question 27

What are the steps of a normal NMJ?

Answer 27

Steps of Normal NMJ 1. Depolarization of pre-synaptic nerve 2. Voltage-gated Ca++ channels open at synapse 3. Ca++ dependent vesicle binding 4. Neurotransmitter (ACh) release 5. Two ACh molecules bind to post-synaptic receptor (MuSK clusters AChR to post-synaptic membrane) 6. Receptor opens allowing Na+ to flow into cell 7. Depolarization of post-synaptic muscle 8. Acetyl-cholinesterase terminates response

Question 28

What are two problems that can occur at the NMJ in myasthenia gravis?

Answer 28

* Antibody binds to AChR → diminished end plate potential * Binding – antibodies may initiate an inflammatory reaction that destroys them * Blocking – antibodies prevent acetylcholine from binding to active site * Modulating – increased endocytosis of receptor * Antibody binds to MuSKR → diminished end plate potential

Question 29

What makes diagnosing myasthenia gravis so challenging?

Answer 29

* Complaints are non-specific (i.e. tiredness, weakness) * Other treatable conditions closely resemble MG * Difficult to catch early due to slow progression of disease

Question 30

What are the mechanisms of the three main tests used to diagnose myasthenia gravis?

Answer 30

* Injection of Edrephorium– inhibits Acetyl cholinesterase → increase in ACh activity * Tensilon Test bad because it was non-specific acetyl cholinesterase inhibitor, causing heart arrhythmias (atropine is required to reverse effects) * Nerve Stimulation Test – consistent nerve stimulation leads to decreased and delayed nerve response * Amplitude of response remains same in normal individuals * Serum AChR-AB Assay Blood Test – checks for AChR ABs are present

Question 31

What is the relationship between the thymus gland and myasthenia gravis?

Answer 31

* Thymus is the site of production for helper T-cells, which help stimulate the B-cells that produce antibodies against the ACh receptor. * Thymus cells are the only known cells to express intact AChR outside of muscle. * These can be recognized as foreign and can start an autoimmune response to AChR throughout the body. * Thymoma can lead to an overexpression of certain antibodies by causing an infiltration of more B cells

Question 32

What are the four main treatments for myasthenia gravis?

Answer 32

* Predisone: immunosuppressant * Pyridostigmine: AchE inhibitor * Azothioprine: immunosuppressant * IVIG: non-specific immunoglobin that boosts immunity by attacking ABs and foreign objects

Question 33

What is the cellular mechanism of glucose transport from the gut to the pancreas?

Answer 33

* From Gut to Pancreas: Carbs are broken into monosaccharides → glucose → transported to SGLT2 on the apical surface from lumen to cell (Na+/Glucose transporter with NaATPase maintaining gradient) → GLUT2 on basolateral surface from cell to blood → blood → to pancreas

Question 34

What is the cellular mechanism of glucose transport from the pancreas in beta cells?

Answer 34

* From Pancreas: GLUT-2 transporters bring glucose into pancreatic B-cells → metabolized to produce ATP via aerobic respiration → increase in [ATP] closes ATP-sensitive K+ channels → cell depolarization → voltage-gated Ca2+ channels open → Ca2+ triggers the release of insulin → tyrosine kinase receptors

Question 35

What is the cellular mechanism of insulin trysoine kinase receptors in the periphery?

Answer 35

* From Tyrosine Kinase Receptors in Periphery: increase in blood [insulin] → insulin binds to tyrosine kinase receptor → cross-phosphorylation of dimer → tyrosine kinase receptor recruits GLUT4 in skeletal tissue to PM → GLUT4 allows passive diffusion of glucose into cell

Question 36

What is the interplay of insulin and glucagon secretion, how does the regulation work, and what are the tissue recceptor sites?

Answer 36

**Liver** * **Fed State (Insulin from beta cells)** * Increase Glycolysis * Increase Glycogen synthesis * Increase Cholesterol synthesis * Increase fatty acid synthesis * Increase triglyceride synthesis * Inhibits glycogenolysis * Inhibits gluconeogenesis * **Fasted State (Glucagon from alpha cells)****​** * Increase gluconeogenesis * Increase glycogenolysis * Increase ketogenesis * Increase amino acid breakdown **Adipose** * **Fed State (Insulin from beta cells)** * Increase triglyceride synthesis * Decrease lipolysis * **Fasted State (Glucagon from alpha cells)** * **​**Increase lipolysis via beta-oxidation **Skeletal Muscle** * **Fed State (Insulin from beta cells)** * Increase protein synthesis * Increase glycogen synthesis * Inhibits proteolysis * Inhibits glycogenolysis **Fasted State (Glucagon from alpha cells)** * Glucagon has no effect on skeletal muscle

Question 37

What is the epidemiology of diabetes mellitus II?

Answer 37

* Epidemiology: thrifty gene hypothesis that genes for fat deposition were advantageous when we were hunter/gathers

Question 38

What are three risk factors of diabetes mellitus type 2?

Answer 38

* Inheritance Factors: some genetic component that makes some individuals more insulin insensitive * Behavioral Factors: eating habits, exercise habits * Environmental Factors: socioeconomic status

Question 39

Define diabetes and list the criteria required to diagnose diabetes mellitus and pre-diabetes?

Answer 39

* Diabetes Mellitus – “sweet urine” * Criteria to Diagnosis: **DMII** * **Fasting Glucose:** \> 126 mg/dL * **Glucose-Tolerance Test:** \> 200 mg/dL * **A1C:** \> 6.5% **Pre-Diabetes** * **Fasting Glucose:** 115-125 mg/dL * **Glucose-Tolerance Test:** 140-199 mg/dL * **A1C:** 5.6-6.5%

Question 40

What is the mechanism of deregulated glucose homeostasis that leads to diabetes mellitus type 2? * Consider: insulin deficiency, insulin resistance, metabolic responses to eating and glucose toxicity

Answer 40

* Decreased insulin sensitivity → decreased glucose reuptake → increased blood glucose → increased beta-cell secretion of insulin → increased lipid/cholesterol synthesis → increased fat deposition on VAT (visceral adipose tissue) on organs * For example, increased fat deposition on heart causes increase in HR and BP * Fat deposition on VAT instead of SAT (subcutaneous adipose tissue) * After years of increased insulin secretion, cells lose sensitivity to insulin becoming insulin resistant exacerbates cycle

Question 41

What is the metabolic syndrome and what are the health consequences of it?

Answer 41

Group of conditions that increase your risk of heart attack and stroke. Chronic state of inflammation: * High blood pressure * High blood sugar * Excess body fat around the waist * Abnormal cholesterol and triglyceride levels

Question 42

What are the seven symptoms of hyperglycemia and what are their mechanisms?

Answer 42

* **Polyphagia** (increased hunger): glucose is unable to enter the cells * **Polydipsia** (increased thirst): result of dehydration from polyuria * **Polyuria** (increased urination): increased blood glucose causes osmotic diuresis * **Weight loss** resulting from dehydration and proteolysis * **Blurred vision**: water is drawn out from eye * **Chronic fatigue** due to lack of cells ability to uptake and use glucose * **Acanthosis nigricans**: increase in circulating insulin results in increase in IGF which results in increased keratinocyte and fibroblast proliferation which results ultimately in increased melanin

Question 43

What is the Class/Action/Side Effects/Elimination/Drug Interactions of Metformin?

Answer 43

* Class: Biguanide * Mechanism of Action: decreases hepatic glucose production by activation of AMPK leading to more GLUT4 going to cell surface, decreases glucose absorption from intestines, increases insulin sensitivity * Side Effects: Not good for people with liver damage, lactic acidosis, hypoglycemia * Elimination: Renally * Drug Interactions: Other renally eliminated drugs

Question 44

What is the Class/Action/Side Effects/Elimination/Drug Interactions of Glipizide?

Answer 44

* Class: Sulfonylurea * Mechanism of Action: Increase insulin release from beta cells by binding to K+ channels, causing depolarization of the cell, opening of Ca2+ gated ion channels, Ca2+ influx, release of insulin into blood * Side Effects: Can cause hypoglycemia because lowers hepatic glucose production * Elimination: Hepatic biotransformation, urine and feces * Drug interactions: Diuretics

Question 45

What are the major steps in the biosynthesis of cholesterol?

Answer 45

1. AAs, FAs, Glucose → Acetyl CoA 2. Acetyl CoA → HMG-CoA 3. HMG-CoA → Mevalonate via HMG-CoA Reductase 4. Mevalonate →→ Cholesterol

Question 46

What is the major regulatory step in the biosyntheis of cholesterol?

Answer 46

HMG-CoA Reductase Is Rate-Limiting Step of Cholesterol Synthesis * Inhibited by: high cholesterol, phosphorylation of AMP dependent-kinase (senses high [AMP], glucagon, epinephrine, statin (HMG-CoA Reductase is phosphorylated) * Stimulated by: insulin

Question 47

Disciss how the SCAP/SCREBP/INSIG complex regulates cholesterol levels.

Answer 47

* High [cholesterol] → SCAP (SREBP cleavage-activating protein) binds to cholesterol, SREBP (sterol regulatory element binding protein), and an INSIG protein at the ER Membrane → inactive state * Low [cholesterol] → SCAP (SREBP cleavage-activating protein) and SREBP (sterol regulatory element binding protein) complex unbind from the INSIG protein at the ER Membrane → SCAP/SREBP transported to Golgi → SREBP is cleaved by S1P and S2P (two proteases) at two different locations, resulting in transcription factor → transcription factor travels to nucleus → increase in cholesterol synthesis

Question 48

Describe the processes that lead to cholesterol turnover and elimination from the body, including the role of bile acids.

Answer 48

1. Fats ingested 2. Bile salts emulsify fats, forming micelles 3. Intestinal lipases degrade triacylglycerols into glycerol and free FAs 4. Free FAs taken up by mucosa and converted back into triacylglycerols in intestinal epithelial cells 5. Triacylglycerols, cholesterol, and apolipoproteins form chylomicrons 6. Chylomicrons move through lymphatic system and bloodstream to tissues 7. Lipoprotein lipases is activated by apoC-II in capillaries releases FAs and glycerol 8. FAs enter cells 9. FAs are oxidized as fuel or converted back to triglycerides for storage

Question 49

What are the two transport mechanisms and what major liproteins are included in each one? * Describe the role of each lipoprotein

Answer 49

**Delivery Transport Mechanism (ApoB containing lipoproteins)** * Chylomicrons (biggest and highest [lipid]) * Can go to the liver – directly drop off FFAs for energy use or membrane rigidity * Can go to the adipose – directly drop off FFAs for storage and then chylomicron remnants go to liver for recycling * VLDL * IDL * LDL * ApoB containing lipoproteins slowly give away their FFAs to cells and get denser and denser **Reverse Cholesterol Transport (ApoA1 containing lipoproteins)** * HDL (smallest and highest [protein]) * Picks up ApoB proteins that dissociated * Interacts with ApoB containing lipoproteins to exchange its cholesterol for TAGs * HDL is returned to the liver

Question 50

What is the role of oxidized LDL in the formation of arthersclerosis?

Answer 50

* LDL leaks between endothelial cells into the wall of the artery → LDL contents (TG, cholesterol) become oxidized → monocytes migrate into wall to clear the oxidized LDL → oxidation of macrophage → macrophage becomes a foam cell → attract more monocytes → creates fatty streaks → inflammatory response → cells pushed into lumen → increase in blood pressure * Foam cells also release IGF → migration of smooth muscle cells from media layer to intima layer → produce collagen → plaque (fibrous cap) → loss of elasticity

Question 51

What are two therpaies/drugs used to lower blood cholesterol?

Answer 51

Statins and Evolocumab

Question 52

What is the Class/Action/Side Effects/Elimination/Drug Interactions of Statins?

Answer 52

* Class: Statin * Action: HMG-CoA reductase inhibitor (competitive) in cholesterol synthesis pathway. * Side effects: mevalonate derivatives will also be decreased (quinones), rhabdomyolysis (muscle degradation), hepatic failure (low enzymes), renal dysfunction due to proteinuria * Elimination: Liver, modified in liver by CYPs, renal excretion * Drug interactions: CYP inhibitors (slow breakdown), lipid-lowering drugs

Question 53

How does evolocumab function to reduce cholesterol?

Answer 53

* Taken in conjunction with statin * PCSK 9 normally binds to LDL receptor and degrades the receptor. Evolocumab actively binds to PCSK 9, increasing the number of LDL receptors. More LDL is taken from the blood into the liver. Therefore, LDL and cholesterol levels decrease.

Question 54

What are the ACC/AHA CV Risk guidelines to assess coronary heart disease?

Answer 54

How to calculate ACC/AHA CV Risk * Variety of factors to predict risk in the next 10 years * Age, gender, race, history of hypertension, smoking, diabetes, current BP, total cholesterol, HDL level, BMI * Plug factors into calculator to give percentage * Treatment recommended for greater than 10% with statin * Only accurate for people between 40-80 yo and total cholesterol of 320 or more.

Question 55

Draw the Urea Cycle and define what its function is.

Answer 55

* Definition of Urea Cycle: Method of excreting urea, a metabolite of protein catabolism.

Question 56

What are the possible enzyme defects that occur in the urea cycle? List: * Disorders are associated with them * Where the enzyme is located * What product accumulates

Answer 56

Question 57

What occurs to the urea cycle during times of starvation (negative nitrogen balance)?

Answer 57

* Starvation/fasting → protein catabolism → amino acid degradation → elevated ketones and ammonia

Question 58

What regulates the urea cycle and what acts as the rate-limiting step?

Answer 58

* Regulation: N-acetylglutamate is an allosteric activator of carbamoyl phosphate synthase * Rate-Limiting Step: carbamoyl phosphate synthase

Question 59

What are the physiological consequences associated with hyperammonemia and what symptoms are associated with these symptoms?

Answer 59

* Excess ammonia → converts alpha-KG to glutamate → glutamate to glutamine → depletes alpha-KG → inhibition of TCA cycle * Leading to symptoms of lethargy (inhibition of TCA), vomiting (toxicity), seizure (NMDA activation by glutamate), cerebral edema (excess glutamate changes osmolality differences across BBB)

Question 60

What are the two sources of ammonia in the blood?

Answer 60

1. Protein Catabolism 2. Gut Bacteria

Question 61

What are the six different treatments associated with the urea cycle and with what enzymes do they correlate (if they do)?

Answer 61

* Hemodialysis: * Removes all the ammonia in the blood * Low-Protein Diet * Any enzyme deficiency requires a low-protein diet because protein catabolism produces ammonia * L-Arginine * Arginosuccinase deficiency - L-arginine bypasses the arginosuccinase step and allows for the urea cycle to produce urea and then pick up new NH3 to excrete as argininosuccinate * Glucose * Ensures that the patient does not starve. * Sodium Benzoate/Sodium Phenylacetate * Provides a method of excretion for high ammonium levels * Liver Transplant * Provides normal enzymes for urea cycle

Question 62

What are the four ethical considerations for newborn screening?

Answer 62

* Reliable diagnostic test * Treatments are available * Early interventions have positive effects * All tests can be avoided on religious basis

Question 63

What are the six state mandated newborn screening tests?

Answer 63

1. Congenital adrenal hyperplasia (CAH) 2. Galactosemia 3. Hemoglobin diseases 4. Maple syrup urine disease (MSUD) 5. Phenylketonuria (PKU) 6. Primary congenital hypothyroidism

Question 64

Where is the branched-chain ketoacid dehydrogenase found?

Answer 64

* BCKD complex is found in the inner membrane of the mitochondria

Question 65

What are the branched chain amino acids and what pathway to their metabolites feed into?

Answer 65

3 BCAAs (L, I, V - essential) → ketoacids → metabolites of TCA cycle

Question 66

What is the general pathway of the BCKD complex and what metabolites are formed?

Answer 66

Question 67

What are the four classes of amino acids mutations and where do the mutations occur?

Answer 67

* “Classic” MSUD (Class 1a): Mutation in gene encoding for E1 alpha subunit * “Intermittent” MSUD (Class 1b): Mutation in gene encoding for E1 alpha subunit * “Thiamine responsive” MSUD (Class 2): Mutation in gene encoding for E2 * Class 3: Mutation in gene encoding for E3 * Extremely rare

Question 68

What cofactors does the BCKD utilize?

Answer 68

* Utilizes 5 cofactors * **T**ender **L**oving **C**are **F**or **N**ancy * TPP (B1 – thiamin) * Lipoic Acid * FAD (B₂ - Ribloflavin) * NAD+ (B₃ - Niacin)

Question 69

How is the BCKD regulated?

Answer 69

Question 70

What is the general mechanism of the BCKD complex or any other dehydrogenase complex?

Answer 70

Question 71

How is Hardy-Weinberg used to calculate carrier frequencies in local Mennonite populations and the population at large?

Answer 71

* Mennonite Population * p² + 2pq + q² = 1 * q² = 1/176 q = 0.0754 * p + q = 1 p = 1 – 0.0754 = 0.9256 * Carrier Frequency = 2pq = 13.9% * Population at Large * p² + 2pq + q² = 1 * q² = 1/185000 q = 0.00232 * p + q = 1 p = 1 – 0.00232 = 0.998 * Carrier Frequency = 2pq = 0.46%

Question 72

What is the founder effect - colony effect?

Answer 72

* Decreased genetic variation due to lack of reproduction outside of a particular community * All members have roots in the same small group of ancestors

Question 73

What is the newborn screening used for MSUD?

Answer 73

* (+) newborn screening using tandem mass spectrometry-based amino acid profiling… * Confirmed with: * Quantitative plasma concentration amino acid analysis to rule out hydroxyprolinemia * GC/MS - on urine samples detects presence of BCKAs

Question 74

What are the clinical presentations of MSUD?

Answer 74

* Initial Presentation in an infant * increased sweet-smelling ear wax within 12-24 hours * Sweet Smelling urine within 5-7 days * Lethargy - vomiting - decreased oral intake - ataxia - * Urine with a syrup odor *(sotolone)* * Ketoacidosis - keto-acid buildup * Neuro Sx: developmental delay and cerebral edema * Particularly due to Leucine toxicity; Leu can cross BBB

Question 75

What are the treatments associated with MSUD?

Answer 75

* Special diet of purified amino acids (limit the ones he cannot breakdown but enough for proper growth and development) * Goals: reduce toxic metabolites; achieve plasma concentrations of branched-chain amino acids, especially leucine; support normal growth; and preserve intellectual function and development. * Thiamine (50 to 200 mg/day) should be given for four weeks to all patients with MSUD

Question 76

What may exacerbate MSUD symptoms?

Answer 76

* Any additional stress on the body leads to protein degradation and in turn a build up of the branched amino acids due to the deficiency of the BCKAD enzyme. Stressors include but not limited to: * Infection * Trauma * Surgery * Extended fasting * Strenuous exercise * Failure to adhere to diet