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USMLE Step 1 High‐Yield Biochemistry Topics
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Biochemistry
High Yield USMLE Step 1 Notes
Welcome to the Biochemistry High-Yield Notes for Step 1.
These are the most commonly tested topics on the exam—ideal for quick review in your last 2 weeks before the exam, when you’re short on time, or when you’re just starting out and want to focus on what is high yield. Created and peer-reviewed by physicians who scored 260+ on Step 1 in a Q&A style to reinforce active learning.
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- Read the question ➔ cover the answer ➔ self-quiz before revealing.
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Table of Contents
VITAMINS
1. A 6-year-old boy from a developing country presents with night blindness and frequent respiratory infections. Eye exam shows conjunctival spots with a foamy appearance. What is the most likely deficiency?
➔ Retinoic acid
- Note: Bitot’s spots, xerophthalmia, and recurrent infections point to vitamin A deficiency.
- Vitamin A is crucial for epithelial integrity and immune function.
2. A 29-year-old woman taking isotretinoin for acne reports nausea, dizziness, and hair thinning. On fundoscopic exam, she shows signs of papilledema. What vitamin toxicity is the likely cause?
➔ Vitamin A
- Note: Hypervitaminosis A can cause intracranial hypertension(presented as papilledema in this patient), alopecia, hepatotoxicity, and is teratogenic — always test for pregnancy before treatment and OCPS are indicated
3. A chronic alcoholic is brought in with confusion, ataxia, and ophthalmoplegia. His glucose level is low, and he is given IV dextrose. His condition rapidly worsens. Diagnosis?
➔ Wernickes encephalopathy
- Note: This patient with ataxia, confusion and ophthalmoplegia has wernickes encephalopathy.
- Always give thiamine before glucose in alcoholics to prevent Wernicke encephalopathy.
- Thiamine is a cofactor for α-ketoglutarate DH, transketolase, and pyruvate DH.
4. A malnourished patient with a history of alcohol use presents with memory loss and confabulation. He does not have eye movement abnormalities or ataxia. What is the most likely diagnosis?
➔ Korsakoff
- Note: Korsakoff psychosis(causing retrograde amnesia with confabulations (making up stories).
- Results from chronic thiamine deficiency and mammillary body damage.
- Irreversible and often follows untreated Wernicke encephalopathy.
5. A 5-year-old child on a corn-based diet presents with symmetric skin lesions in sun-exposed areas, diarrhea, and confusion. What vitamin is most likely deficient?
➔ Niacin
- Note: Pellagra = 3 D’s: dermatitis (usually broad collar rash), diarrhea, dementia.
- Also seen in Hartnup disease (↓ tryptophan absorption), isoniazid use (↓ B6-dependent niacin synthesis) and carcinoid syndrome (consumption of tryptophan used in making serotonin).
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6. A patient on high-dose niacin for hyperlipidemia complains of painful facial flushing after each dose. What substance mediates this reaction?
➔ Prostaglandin
- Note: Niacin-induced flushing is prostaglandin-mediated.
- Pretreatment with aspirin reduces symptoms.
- Niacin also increases uric acid (→ gout risk) and causes hyperglycemia.
7. A woman treated for TB develops numbness in her hands and feet. She also complains of irritability. Which vitamin deficiency is most likely responsible?
➔ Pyridoxine B6
- Note: TB patients are on RIPE therapy (Rifampin, Isoniazid, Pyrazinamide, Ethambutol)
- Isoniazid inhibits vitamin B6 (pyridoxine), a cofactor in neurotransmitter synthesis and transamination.
- Deficiency → peripheral neuropathy, seizures.
8. A child has dry skin, hair loss, and irritability. He consumes raw egg shakes daily as part of a bodybuilding diet. What vitamin is most likely deficient?
➔ Biotin B7
- Note: Avidin in raw egg whites binds biotin and prevents its absorption.
- Biotin is a cofactor for carboxylases in gluconeogenesis (Pyruvate carboxylase) and FA synthesis (acetyl Co-A carboxylase).
9. A 26-year-old pregnant woman presents late to prenatal care. Her baby is later born with a neural tube defect. What vitamin deficiency is most likely responsible?
➔ Folate B9
- Note: Folate (B9) is essential for DNA synthesis. Deficiency during early pregnancy can lead to neural tube defects such as spina bifida and anencephaly.
- Supplementation is recommended preconceptionally.
10. A 70-year-old man presents with fatigue and glossitis. Labs show macrocytic anemia with hypersegmented neutrophils. Neurologic exam is normal. Which vitamin is most likely deficient?
➔ Folate
- Note: Folate deficiency caused by poor diet (stores deplete in weeks), alcoholism, pregnancy, drugs like methotrexate and phenytoin.
- Folate deficiency presents with Megaloblastic anemia with no neurological signs.
- Both folate and vitamin B12 deficiencies → megaloblastic anemia + ↑ homocysteine
11. A 60-year-old woman presents with numbness in her legs, difficulty walking, and loss of vibration sense. She also has macrocytic anemia and elevated methylmalonic acid levels. What is the most likely cause?
➔ Cobalamin
- Note: Vitamin B12 (cobalamin) deficiency causes subacute combined degeneration➞ demyelination of corticospinal tracts( weakness and UMNL symptoms), dorsal columns(ataxia, loss proprioception ), and spinocerebellar tracts.
- B12 deficiency → ↑ methylmalonic acid + neurologic symptoms (e.g., paresthesia, ataxia)
- B12 deficiency: develops over years, especially in vegans without supplementation (Folate is found in leafy greens, not typically deficient in vegan diets)
12. A 52-year-old woman presents with fatigue, paresthesias, and glossitis. Laboratory tests reveal macrocytic anemia. Further workup shows anti–intrinsic factor antibodies. Which of the following deficiencies is most likely contributing to her symptoms?
➔ Cobalamin
- Note: Intrinsic factor is required for B12 absorption in the terminal ileum.
- Pernicious anemia presents with antibodies against intrinsic factor → B12 absorption, megaloblastic anemia and paraesthesia.
- Other B12 deficiency causes include: Crohn’s disease(terminal ileitis and resections), vegan diet, and gastric bypass.
13. A patient with vitamin B12 deficiency is treated with folate only. What complication may worsen as a result?
➔ Neuropathy
- Note: Giving folate alone may improve the anemia but consumes B12 and worsen the neurologic damage in B12 deficiency. Always check both before treating.
14. A 9-month-old exclusively breastfed infant is brought in with bowed legs and delayed closure of fontanelles. X-ray shows metaphyseal cupping and fraying. What vitamin deficiency is most likely responsible?
➔ Vitamin D
- Note: Rickets is due to vitamin D deficiency in children.
- Breast milk lacks adequate vitamin D, so supplementation is recommended—especially in infants with limited sun exposure.
- Fat malabsorption leads to loss of fat soluble vitamins including vitamin D.
- Vitamin D deficiency can present with bony pains in adults.
15. A middle-aged man with sarcoidosis develops hypercalcemia and kidney stones. His PTH is low, but 1,25-dihydroxyvitamin D is elevated. What is the cause of his hypercalcemia?
➔ Macrophages
- Note: In granulomatous diseases, macrophages express 1-α hydroxylase, leading to unregulated vitamin D activation and hypercalcemia. This bypasses normal PTH regulation.
- Steroid treatment decreases the 1-α hydroxylase.
16. A premature infant develops necrotizing enterocolitis and is treated with prolonged parenteral nutrition. He later develops hemolytic anemia and decreased deep tendon reflexes. What vitamin deficiency is most likely?
➔ Vitamin E
- Note: Vitamin E protects RBCs and neurons from oxidative damage. (vitamins A,C,E are antioxidants that clear oxygen radicals).
- Fat malabsorption in cystic fibrosis can cause Vitamin E deficiency (also vitamin A,K,D).
- Vitamin E deficiency presents with hemolytic anemia and posterior column demyelination (mimics B12 deficiency but no methylmalonic acid elevation and hemolytic anemia instead of megaloblastic anemia).
17. A patient with fat malabsorption due to cystic fibrosis develops prolonged PT and easy bruising. He is given warfarin and experiences excessive bleeding. Which vitamin deficiency most likely contributed?
➔ Vitamin K
- Note: Vitamin K is required for γ-carboxylation of clotting factors II, VII, IX, and X. Deficiency → bleeding.
- It should be administered after delivery to prevent hemorrhagic disease of the newborn.
18. A healthy term newborn is delivered vaginally without complications. He receives an intramuscular injection of vitamin K shortly after birth to prevent which of the following?
➔ Intraventricular hemorrhage.
- Note: Neonates have low vitamin K levels due to sterile gut and poor placental transfer.
- Vitamin K injection prevents hemorrhagic disease of the newborn. (Broad spectrum antibiotics also kill the vitamin K producing bacteria causing deficiency).
19. A 64-year-old man with chronic alcoholism and poor diet presents with fatigue, swollen bleeding gums, and multiple bruises on his legs. PT and PTT are normal, but bleeding time is prolonged. What deficiency is most likely?
➔ Vitamin C
- Note: Vitamin C is a necessary cofactor hydroxylation of proline and lysine residues in the RER which is necessary for making collagen.
- Scurvy results from defective collagen hydroxylation due to vitamin C deficiency.
- Bleeding time is affected due to vessel fragility, not coagulation factor defects.
- Vitamin deficiency also can cause corkscrew hair and usually happens in malnourished elderly “tea and toast diet”
20. A patient takes megadoses of vitamin C as a daily supplement. He later develops flank pain and hematuria. What is the most likely cause of his symptoms?
➔ Nephrolithiasis
- Note: Vitamin C excess increases oxalate production, predisposing to calcium oxalate nephrolithiasis.
21. A young boy presents with periorificial and acral dermatitis, diarrhea, and alopecia. His symptoms worsen after weaning. His serum alkaline phosphatase is low. What is the most likely condition?
➔ Acrodermatitis enteropathica
- Note: Zinc is essential for metalloproteinase activity(removes temporary type III collagen in granulation tissue) and early wound healing.
- Acrodermatitis enteropathica is an inherited zinc absorption disorder and associated with: Loss of smell (anosmia), loss of taste, immune dysfunction, infertility and dermatitis.
22. A 45-year-old man is brought to the emergency department after being found unconscious suspected to have ingested methanol. He is hypotensive and tachypneic with a high anion gap metabolic acidosis. He is given fomepizole. What is the mechanism of action of the antidote?
➔ Inhibition of Alcohol dehydrogenase
- Note: Alcohol dehydrogenase: converts ethanol, methanol, ethylene glycol → toxic metabolites
- Fomepizole: antidote for methanol & ethylene glycol toxicity → inhibits alcohol dehydrogenase
23. An alcoholic patient presenting acutely with hypoglycemia with lactic acidosis and hepatomegaly. What is the primary cause of the impaired TCA cycle activity?
➔ High NADH
- Note: Alcohol dehydrogenase is the main enzyme of alcohol metabolism and needs NADH to work → consumes high amounts of NAD⁺ → ↑ NADH/NAD⁺ ratio from ethanol → inhibits gluconeogenesis (NAD⁺ dependant) → hypoglycemia
- ↑ NADH and consumption of NAD⁺ impairs other NAD⁺-dependent reactions (e.g., TCA, β-oxidation) and shunts pyruvate to lactate (lactic acidosis) and DHAP to glycerol-3-P (more triglyceride formation and fatty liver).
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Collagen Synthesis and Related Disorders
24. A patient with easy bruising and hypermobile joints is found to have defective collagen cross-linking. What enzyme is impaired?
➔ Lysyl oxidase
- Note: Lysyl oxidase cross-links collagen fibrils which Requires copper as a cofactor.
Defects seen in Ehlers-Danlos syndrome which presents with hyperextensible skin, joint hypermobility, and easy bruising due to defective collagen synthesis.
25. A child presents with brittle bones and blue sclerae. Genetic testing shows a defect in type I collagen. What is the most likely diagnosis?
➔ Osteogenesis imperfecta
- Note: Type I collagen defect. Features include blue sclera (buzzy image), multiple fractures, and hearing loss.
26. A 25-year-old man with Marfan syndrome presents with sudden-onset chest pain radiating to the back. His blood pressure is asymmetric in both arms. What life-threatening complication should be suspected?
➔ Aortic dissection
- Note: Marfan syndrome increases the risk of aortic dissection due to cystic medial necrosis of the aorta.
- Regular cardiovascular monitoring is essential.
- Other features include mitral valve prolapse, ectopia lentis (upward lens dislocation), and spontaneous pneumothorax.
27. A researcher studies different types of collagen and notes that one is essential for cartilage, another for skin, and another for basement membranes. Which types correspond to these locations?
➔ Type II, Type I, Type IV
- Note: Type I → Bone, skin, tendon (bone = type I),
- Type II → Cartilage (cartwolage), can be damaged in osteoarthritis.
- Type III → Reticulin (blood vessels, skin),
- Type IV → Basement membrane (floor of epithelium).
- Defects: Type I → Osteogenesis imperfecta, Type III → Ehlers-Danlos, Type IV → Alport syndrome and Good pasture syndrome (antibodies against type IV collagen).
28. A malnutritioned 4-year-old child is brought to the clinic due to poor wound healing and gum bleeding. Physical exam shows multiple petechiae on the lower limbs. He prefers a diet of white bread and canned foods. Deficiency of which cofactor most likely impaired hydroxylation of proline and lysine residues during collagen synthesis in this patient?
➔ Vitamin C
- Note: Vitamin C is required for hydroxylation of proline and lysine residues in the RER. (Glycine is the most common amino acid in collagen)
29. A tall man with long limbs, hypermobile joints, and upward lens dislocation presents with chest pain. What is the likely diagnosis?
➔ Marfan syndrome
- Note: Autosomal dominant mutation in fibrillin-1(not elastin itself).
- Major cause of death is aortic dissection/rupture due to cystic medial necrosis of the aorta.
- Mitral valve prolapse, upwards lens dislocation and aortic regurgitation are also common.
- Homocystinuria is a patient with downward lens dislocation (vs upward in Marfan syndrome), marfanoid body habitus and more thrombosis risk
30. A woman presents with easy bruising, hyperextensible skin, and joint hypermobility. Genetic testing reveals faulty collagen synthesis. What syndrome does she have?
➔ Ehlers-Danlos
- Note: Ehlers-Danlos classically is a defect in type III collagen, increasing risk of delayed wound healing, arterial rupture and berry aneurysm rupture (presenting with sudden subarachnoid hemorrhage)
31. A lab wants to detect a specific DNA mutation in a patient’s genome. Which technique uses labeled DNA probes to detect specific sequences on a membrane?
➔ Southern blot
- Note: Southern = DNA, Northern = RNA, Western = protein. (SNoW DRoP mnemonic each letter correlates with the tested material).
Carbohydrate Metabolism
32. A patient with pyruvate dehydrogenase deficiency develops neurologic deficits and lactic acidosis. What amino acid should be increased in the diet to bypass the defect?
➔ Lysine
- Note: In PDH deficiency, pyruvate cannot be converted to acetyl-CoA, causing pyruvate buildup and lactic acidosis;
- Only ketogenic amino acids (lysine and leucine) bypass this block and do not generate lactate.
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33. A child with recurrent vomiting and lethargy after high-carbohydrate meals is found to have elevated alanine and lactate. What enzyme is likely deficient?
➔ Pyruvate dehydrogenase
- Note: PDH converts pyruvate to acetyl-CoA. Deficiency leads to lactic acidosis, neurotoxicity, elevated alanine and Fasting Hypoglycemia.
- This enzyme complex requires 5 co-factors (vitamin B1, B2, B3, B5, and lipoic acid).
34. A researcher develops a material that inhibits fructose-2,6-bisphosphate. What metabolic process will decrease?
➔ Glycolysis
- Note: Fructose-2,6-bisphosphate activates PFK-1 (key glycolytic enzyme) and inhibits gluconeogenesis via FBPase-1 inhibition.
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35. A 3-month-old infant presents with hepatomegaly, fasting hypoglycemia, and lactic acidosis. Blood tests reveal elevated triglycerides and uric acid. Liver biopsy shows abundant glycogen accumulation. Genetic testing reveals a deficiency in a gluconeogenesis enzyme responsible for catalyzing an irreversible step. What’s the deficient enzyme?
➔ Glucose-6-phosphatase
- Note: Irreversible Enzymes of Gluconeogenesis:
- Glucose-6-phosphatase(also last step in glycogenolysis): G6P → Glucose (liver/kidney only)and deficient in von gierke(check Q 56 for the presentation)
- Pyruvate carboxylase: Pyruvate → Oxaloacetate (mitochondria)
- Phosphoenolpyruvate carboxykinase (PEPCK): Oxaloacetate → PEP (cytosol)
- Fructose-1,6-bisphosphatase: F1,6BP → F6P (rate-limiting step)
36. During an experiment, a researcher measures ATP generation from FADH₂ produced in the Krebs cycle. The FADH₂ enters the electron transport chain via which of the following complexes?
➔ Complex II
- Note: Complex I: NADH → NAD⁺ (1 NADH = 2.5 ATP)
Complex II: FADH₂ produced from Succinate dehydrogenase in krebs cycle(1 FADH₂ = 1.5 ATP)
Complex III: Transfers e⁻ via cytochrome c
Complex IV: O₂ → H₂O inhibited by cyanide and CO
Complex V (ATP synthase)
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37. A 42-year-old man is brought to the emergency department after suspected exposure to toxic fumes in an enclosed space. He has seizures and loses consciousness. His symptoms are due to inhibition of mitochondrial Complex IV. What is the toxin responsible for the presentation?
➔ Cyanide
- Note: Complex IV in the ETC cycle is inhibited by cyanide and carbon monoxide poisoning.
- Cyanide poisoning presents with altered mental status, seizures, lactic acidosis, and a characteristic “bitter almond” odor on the breath.
38. A 7-month-old infant is brought to the emergency department for vomiting and lethargy. The symptoms started after the introduction of fruit juice and honey into the diet. Physical exam shows hepatomegaly and pallor. Blood glucose is low, and urine is positive for reducing substances. Which of the following enzymes is most likely deficient in this patient?
➔ Aldolase B
- Note: Hereditary fructose intolerance with Aldolase B deficiency → causes trapping of fructose-1-P → depleting phosphate and ATP → hypoglycemia and hepatomegaly .
- Symptoms after 6 months with initiation of fructose sugar in the diet. NO CATARACT(differentiates it from Classic galactosemia)
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39. A 8 month old kid has reducing substances in urine but is otherwise asymptomatic. What enzyme is deficient?
➔ Fructokinase
- Note: Essential fructosuria is benign. Fructose can’t be phosphorylated → spills into urine
- Hexokinase becomes the primary pathway for converting fructose to fructose-6-phosphate → Asymptomatic.
40. A 2-month-old infant develops vomiting, jaundice, cataract and hepatomegaly. Urine shows reducing sugars. What is the most likely cause?
➔ Galactose-1-phosphate uridyltransferase
- Note: Classic galactosemia is a life-threatening disorder with Toxic accumulation of galactose-1-phosphate → depleting phosphate and ATP → hypoglycemia and hepatomegaly.
- Avoid galactose and lactose. Increases the risk of E. coli sepsis.
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41. A 6-year-old boy is brought to the clinic by his parents due to chronic bloating and diarrhea. His symptoms worsen after consuming dairy products.His mother reports that she had similar issues during childhood.Which of the following is the most likely underlying cause of this patient’s symptoms?
➔ Decreased brush border enzyme activity
- Note: Hereditary lactase deficiency): ↓ lactase at intestinal brush border and a problem in lactose metabolism
- Symptoms: bloating, flatulence, watery diarrhea (osmotic), abdominal cramps after milk consumption
- Stool: ↓ pH(due to acid production), positive reducing substances
- Secondary lactase deficiency can follow GI infections (e.g., rotavirus → damaged enterocytes)
- Management: Lactose-free diet or lactase enzyme supplementation
42. A child has cataracts but no liver symptoms. Reducing sugars are found in urine. What enzyme is likely deficient?
➔ Galactokinase
- Note: Galactokinase deficiency is a milder galactose metabolism disorder. Cataracts result from galactitol accumulation.
Fat Metabolism
43. A newborn with lethargy and hypoglycemia has no ketones in urine during fasting. Administration of Long Chain Fatty acids and medium chain fatty acids does not increase glucose. What enzyme is most likely deficient?
➔ Acyl-CoA dehydrogenase deficiency
- Note: Acyl-CoA dehydrogenase deficiency impairs β-oxidation of both MCFA and LCFA.
- Fasting hypoketotic hypoglycemia is always the indication of FA oxidation problem → Avoid fasting.
44. A 3-month-old has hepatomegaly and hypoketotic hypoglycemia. Administration of Long Chain FA does not increase glucose while medium chain fatty acids increase glucose. What transport defect is most likely?
➔ Carnitine shuttle
- Note: LCFA depends on carnitine shuttle to enter the mitochondria while medium chain fatty acids enter directly so Carnitine deficiency blocks long chain fatty acids entry into mitochondria → ↓ β-oxidation and ketone synthesis.
○ LCFA accumulation occurs in carnitine deficiency
○ MCFA+LCFA accumulation in B-oxidation defect (previous question)
○ VLCFA in peroxisomal defect
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45. A diabetic patient has fruity-smelling breath and rapid breathing. What compound causes the odor?
➔ Acetone
- Note: Ketone bodies: acetoacetate, β-hydroxybutyrate, and acetone. In DKA and starvation, ketogenesis increases due to high glucagon and low insulin.
46. After several days of fasting, what is the brain’s primary fuel?
➔ Ketones
- Note: Brain switches from glucose to ketone bodies (mainly β-hydroxybutyrate) after ~3 days to preserve muscle mass.
- Between the meals: glycogenolysis (major)
- Starvation for more than 24 hours: release of free fatty acids from adipose tissue, muscle, and liver use FFA as fuel (brain still uses glucose).
- Starvation for more than three days: the brain starts using ketone bodies and after depletion from adipose stores, vital protein degradation increases for energy.
47. A 22-year-old man has multiple yellow papules on his knees. Labs show markedly elevated LDL. What is he at increased risk for?
➔ Myocardial infarction
- Note: Familial hypercholesterolemia (autosomal dominant) is caused by LDL receptor or ApoB-100 defects. Early coronary artery disease is common.
- Statin is indicated for hypercholesterolemia while fibrate is indicated in familial hypertriglyceridemia.
48. A 4-year-old boy is brought in for evaluation of multiple eruptive xanthomas on his buttocks and elbows. Labs show elevated triglycerides and a creamy layer in plasma after overnight refrigeration. What is the diagnosis?
➔ Familial hyperchylomicronemia
- Note: Familial hyperchylomicronemia is an Autosomal Recessive disorder with deficiency in Lipoprotein lipase or ApoC-II leading to → ↑ Chylomicrons, ↑ TGs → pancreatitis + eruptive xanthomas
– Milky/creamy layer on plasma sample is a keyword!
49. A 6-month-old infant is evaluated for failure to thrive and chronic diarrhea. His stools are foul-smelling and float in the toilet. Physical exam shows decreased muscle tone. Fundoscopy reveals retinitis pigmentosa. Labs reveal low cholesterol and undetectable ApoB. What’s the diagnosis?
➔ Abetalipoproteinemia
- Note: Abetalipoproteinemia is an Autosomal Recessive disorder with failure of ApoB formation → ↓ chylomicrons, VLDL, LDL
- Symptoms: failure to thrive, steatorrhea, acanthocytosis (RBCs with projections), retinitis pigmentosa, Intestinal biopsy shows lipid-laden enterocytes(intestinal wall filled with clear white droplets) and Fat-soluble vitamin deficiency (A,D,E,K).
50. A 6-hour fasting blood sample is taken from a healthy 25-year-old man. He is then given a carbohydrate-rich meal. Shortly after the meal, insulin secretion increases. Which of the following enzymes is most likely activated in response to this fed state?
➔ Glycogen synthase
- Note: Fed state (high insulin) → promotes anabolism: glycogenesis, glycolysis, fatty acid synthesis.
- Fasting state (Low insulin) → promotes catabolism and energy production: gluconeogenesis, glycogenolysis, fatty acid oxidation
| Fed State (High Insulin) | Fasting State (High Glucagon, Epinephrine, Cortisol, GH) |
|---|---|
| ↑ Glycogenesis (glycogen synthase activated) | ↑ Glycogenolysis (glycogen phosphorylase activated) |
| ↑ Glycolysis (PFK-1, pyruvate kinase activated) | ↑ Gluconeogenesis (PEP carboxykinase, fructose-1,6-bisphosphatase activated) |
| ↑ Fatty Acid Synthesis (acetyl-CoA carboxylase, fatty acid synthase activated) | ↑ Fatty Acid Oxidation (carnitine shuttle, hormone-sensitive lipase activated) |
| ↓ Lipolysis (hormone-sensitive lipase inhibited) | ↑ Lipolysis (hormone-sensitive lipase stimulated) |
51. A 16-year-old girl with newly diagnosed type 1 diabetes mellitus is started on insulin therapy. After administration of insulin, glucose uptake increases in her skeletal muscles. Which of the following glucose transporters is primarily responsible for this insulin-stimulated glucose uptake?
➔ GLUT-4
- Note: GLUT-4 is the only insulin-dependent glucose transporter → found in skeletal muscle and adipose tissue. Insulin triggers its translocation to the cell membrane, increasing glucose uptake.
- GLUT-2 : on Liver, pancreas (β-cells) → Insulin independent with low affinity, high capacity and responsible for insulin secretion
- GLUT-5: on Small intestine, sperm → acts as Fructose transporter (not glucose!)
- SGLT-1 / SGLT-2 (Not GLUT) : Intestine (SGLT-1), proximal tubule (SGLT-2) → Na⁺-dependent secondary active co-transport for absorption of glucose
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Amino acid metabolism
52. A 3-month-old infant is brought in due to developmental delay and seizures. Physical exam shows fair skin, musty body odor, and microcephaly. What enzyme is most likely deficient?
➔ Phenylalanine hydroxylase
- Note: Phenylketonuria is a deficiency in Phenylalanine hydroxylase leads to → ↑ phenylalanine
Can also be due to tetrahydrobiopterin (BH4) deficiency (cofactor for Phenylalanine hydroxylase) → Malignant PKU with ↑ phenylalanine + ↓ serotonin, Melatonin to differentiate from classic PKU - Presents with: intellectual disability, musty odor, fair skin
- Diet: ↓ phenylalanine, ↑ Tyrosine (will be essential amino acid) and BH4
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53. A 3-day-old neonate becomes lethargic, begins vomiting, and has tachypnea. Labs show elevated ammonia levels and lactic acid levels. Urine orotic acid is low. Which of the following enzymes is most likely deficient?
➔ Carbamoyl phosphate synthetase I
- Note: CPS1: First step of urea cycle (mitochondrial) → no formation of carbamoyl phosphate → low orotic acid, hyperammonemia
- OTC deficiency → carbamoyl phosphate accumulation→ high orotic acid and hyperammonemia
- Arginase deficiency → high arginine
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54. A 16-year-old boy with developmental delay is brought to the emergency department with sudden-onset shortness of breath and left leg swelling. Physical exam shows bilateral downward lens dislocation, dyspnea, and tenderness with edema in the left calf. Lab studies show: (↑ Methionine, ↑ Homocysteine, and↓ Cystathionine). What’s the deficient enzyme?
➔ Cystathionine β-synthase
- Note: Cystathionine β-synthase deficiency → homocystinuria (AR): ↑ homocysteine, ↑ methionine
- Presents with Marfanoid habitus(looks like marfan but not marfan), downward lens dislocation, intellectual disability, thrombosis (DVT/PE)
- Labs: ↑ homocysteine, ↓ cystathionine/cysteine, ↑ Methionine
- Treatment: B6, folate, B12, dietary methionine restriction
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55. A 3-day-old neonate becomes lethargic and irritable. He is noted to have poor feeding, vomiting, and a sweet-smelling urine odor. On exam, he is hypotonic with intermittent episodes of dystonia. Lab tests show elevated levels of leucine and its ketoacids. What is the deficient enzyme?
➔ Branched-chain α-ketoacid dehydrogenase
- Note: Maple syrup urine disease presents with deficiency of Branched-chain α-ketoacid dehydrogenase
- It’s one of the organic acidemias that presents with severe acid accumulation and leads to → Inhibition of gluconeogenesis → fasting hypoglycemia, high ketoacidosis and high anion gap metabolic acidosis Also Inhibits urea cycle → hyperammonemia
- Presents with: Sweet/burnt sugar-smelling urine, Poor feeding, lethargy, vomiting
- Treatment: Restriction of branched-chain AAs + thiamine (cofactor) supplementation
Glycogen Storage Diseases (GSDs)
56. A 4-month-old has severe fasting hypoglycemia, hepatomegaly, and lactic acidosis. What enzyme is deficient?
➔ Glucose-6-phosphatase
- Note: Von Gierke disease (Type I) is caused by Glucose-6-phosphatase → Inhibited gluconeogenesis.
- Von Gierke disease presents with hepatomegaly, hyperlipidemia, hyperuricemia and severe fasting hypoglycemia, managed by avoiding fasting and giving frequent cornstarch.
57. A 6-month-old has cardiomegaly, hypotonia, and macroglossia. Death occurs due to heart failure. What disease is this?
➔ Pompe
- Note: Pompe disease (Type II) is caused by acid α-glucosidase deficiency (acid maltase). Only GSD with lysosomal involvement and presents with hypertrophic cardiomyopathy.
58. A 26-year-old man presents with a history of muscle cramps, fatigue, and dark-colored urine after strenuous exercise. He reports the symptoms improve if he rests briefly and then resumes at a slower pace. Physical exam is unremarkable. Labs show elevated creatine kinase and myoglobinuria. Blood glucose is normal. Muscle biopsy reveals increased glycogen content. What‘s the diagnosis?
➔ McArdle disease
- Note: Deficiency: Muscle glycogen phosphorylase
- Symptoms: Exercise intolerance, cramps, myoglobinuria, normal blood glucose and elevated CK. Muscle involvement only, no hepatomegaly
- Second-wind phenomenon: Symptom relief after brief rest due to switch to fatty acid oxidation
Von Gierke disease:
- Deficiency: Glucose-6-phosphatase. Primarily affects liver, not muscles
- Symptoms: Fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia
Lysosomal Storage Diseases (LSDs)
59. An infant is evaluated for poor growth and delayed developmental milestones. she has coarse facial features, hypotonia, bilateral inguinal hernias, and joint laxity. Labs show high multiple lysosomal enzymes in the plasma. What’s the diagnosis?
➔ Phosphorylation of lysosomal enzymes with mannose-6-phosphate
- Note: I cell disease is deficiency of N-acetylglucosaminyl-1-phosphotransferase → leads to Golgi(main issue is in golgi not lysosomes) failing to add mannose-6-phosphate to lysosomal enzymes → These enzymes can’t be directed to lysosomes, so they’re secreted extracellularly instead
- Key lab: ↑↑ lysosomal enzymes in plasma.
60. A child has hepatosplenomegaly, anemia, and bone pain. Bone marrow shows macrophages with crumpled tissue paper appearance. What enzyme is deficient?
➔ Glucocerebrosidase
- Note: Gaucher disease (most common Lysosomal Storage Disease) is a deficiency of Glucocerebrosidase → accumulation of Glucocerebroside.
- Patient Presents with Hepatosplenomegaly, pancytopenia, bone crises, avascular necrosis of the femoral head and the Lipid-laden macrophages “crumpled tissue paper appearance” as a keyword!
61. An infant with developmental regression has cherry-red macula and no hepatosplenomegaly. What is the most likely diagnosis?
➔ Tay-Sachs
- Note: Tay-Sachs is a Hexosaminidase A deficiency → leads to accumulation of GM2 ganglioside. Unlike Niemann-Pick, liver is spared.
62. A child with neurodegeneration, hepatosplenomegaly,foam cells(lipid-laden macrophages) and cherry-red macula dies in early childhood. What lipid is accumulated?
➔ Sphingomyelin
- Note: Niemann-Pick disease is a deficiency of sphingomyelinase → accumulation of Sphingomyelin.
- Differentiate from Tay-Sachs by the presence of hepatosplenomegaly.
63. A boy with angiokeratomas, acroparesthesias, and hypohidrosis develops renal failure. What enzyme is deficient?
➔ α-galactosidase A
- Note: Fabry disease is X-linked recessive with a deficiency α-galactosidase A → accumulation of ceramide trihexoside.
- Presents with angiokeratomas, renal and cardiac disease.
64. A child has coarse facial features, hepatosplenomegaly, and corneal clouding. What enzyme is deficient?
➔ Iduronidase
- Note: Hurler syndrome (Mucopolysaccharidoses I) is a Deficiency of α-l-iduronidase → Accumulation of heparan and dermatan sulfate.
- Presents with developmental delay, airway obstruction and CORNEAL CLOUDING.
65. A boy has aggressive behavior, no corneal clouding, and hepatosplenomegaly. What syndrome is this?
➔ Hunter
- Note: Hunter syndrome (Mucopolysaccharidoses II) is a Deficiency of Iduronate-2-sulfatase → Accumulation of heparan and dermatan sulfate.. X-linked recessive.
- Milder than Hurler and NO CORNEAL CLOUDING . “Hunters see clearly and shoot aggressively for the X.”
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MOLECULAR BIOCHEMISTRY
66. A researcher examining a cell under an electron microscope notices densely packed chromatin that appears darkly stained. What is the likely transcriptional activity of this chromatin region?
➔ Inactive
- Note: Euchromatin: active, light, less dense, more transcription and formed by acetylation of histones (acetylation = more transcription = more translation and more proteins ).
- Heterochromatin: less active, more dense, less transcription and formed by methylation of histones (Methylation = less transcription = less translation and less proteins).
67. A researcher studying chromatin structure observes a “beads on a string” pattern under an electron microscope. This structure is typical of active chromatin undergoing transcription. What do the bead-like structures represent?
➔ Histones
- Note: Histones mediate the compaction of the DNA in a “string of beads ” appearance with H1 linking in between
68. A geneticist isolates a sample of circular, double-stranded DNA with no associated histone proteins. The DNA codes for components of the electron transport chain. Which cellular structure is the most likely source?
➔ Mitochondria
- Note: Mitochondria is the only organelle with separate DNA outside the nucleus and different from the normal DNA (no histones therefore = no acetylation /no methylation)
69. A mutation prevents the binding of general transcription factors to upstream regulatory elements in a eukaryotic gene. Which sequences are most likely affected?
➔ TATA box
- Note: TATA and CAAT boxes are promoter sequences needed to initiate transcription.
- Enhancers: Activators (proteins) bind enhancers to promote transcription can be far upstream, downstream.
- Silencer: Repressors bind silencers to decrease transcription
70. A cancer patient receiving chemotherapy develops severe gastrointestinal symptoms. He is being treated with 5-fluorouracil. What metabolic pathway is most likely being inhibited?
➔ Pyrimidine
- Note: 5-FU inhibits thymidylate synthase, blocking dTMP synthesis. This disrupts DNA synthesis, particularly affecting rapidly dividing cells → BM suppression
71. A patient with systemic lupus erythematosus (SLE) is prescribed azathioprine. Several days later, he developed bone marrow suppression. He is also found to be taking allopurinol. What metabolic effect likely caused this adverse reaction?
➔ Accumulation
- Note: Allopurinol inhibits xanthine oxidase, which normally metabolizes 6-mercaptopurine (active form of azathioprine) → toxicity.
- Azathioprine inhibits de novo purine synthesis (Glutamine is the nitrogen donor for the purine formation)
Created with BioRender.com
72. A boy with developmental delay, self-mutilation(hand/lip biting or smashing), and orange urine crystals has hyperuricemia. HGPRT deficiency is suspected. What metabolite is most likely decreased?
➔ Guanine
- Note: Lesch-Nyhan syndrome results from HGPRT deficiency, blocking conversion of guanine and hypoxanthine back to GMP/IMP. So guanine is degraded instead of being salvaged.
- This leads to purine loss, excess uric acid, and upregulation of de novo synthesis via PRPP amidotransferase.
Created with BioRender.com
73. A boy with Lesch-Nyhan syndrome has been prescribed a medication to reduce uric acid levels. Which enzyme’s activity is directly inhibited by this treatment?
➔ Xanthine oxidase
- Note: Allopurinol and febuxostat inhibit xanthine oxidase, reducing uric acid formation from hypoxanthine and xanthine.
74. A 3-year-old boy has developmental delay and failure to thrive. Genetic testing reveals a single base substitution resulting in the (UAA) codon in a gene. Which of the following best describes the type of mutation found?
➔ Nonsense mutation
- Note: Early insertion of the stop codons (UGA-UAG-UAA) results in the formation of truncated short non functional proteins.
75. A 3-month-old infant presents with hypotonia and feeding difficulties. Genetic testing reveals a mutation in the SMN1 gene causing spinal muscular atrophy. The mutation involves deletion of a single nucleotide in the coding region of the gene. Which of the following best describes the consequence of this mutation?
➔ Truncated non-functional protein
- Note: Frameshift mutations are caused by insertion or deletion of nucleotides not in multiples of 3 → Alters the reading frame, changing every amino acid downstream.
- Often introduces premature stop codons, leading to nonfunctional or truncated proteins, Duchenne muscle dystrophy is a classic example.
Created with BioRender.com
76. A 10-year-old girl presents with growth delay and unusual facial features. Whole exome sequencing reveals a mutation that disrupts the removal of introns from pre-mRNA.Which type of mutation most likely explains her symptoms?
➔ Splice site mutation
- Note: Exons are the coding regions of a gene that are expressed in the final mRNA, while introns are non-coding segments that are spliced out during RNA processing via spliceosome.
- Splice site mutations usually are in the INTRONs (not in the exons) closest to the exons (sites where the spliceosome bind) → abnormal splicing
- Pre-mRNA maturation into mRNA include:
1- 5´ cap
2-Splicing
3-Poly A tail
Created with BioRender.com
77. A 7-year-old child presents with multiple colon polyps and a family history of colorectal cancer. Genetic testing reveals a defect in mismatch repair enzymes. What hereditary syndrome is most likely?
➔ Lynch
- Note: Lynch syndrome (HNPCC) is associated with MSH2 and MLH1 gene mutations (crucial for mismatch repair).
- It increases risk for colon, endometrial, and ovarian cancers.
78. A child presents with photosensitivity, dry skin, and multiple skin cancers. A defect in which DNA repair mechanism is likely?
➔ Nucleotide excision repair
- Note: Nucleotide excision repair removes bulky DNA lesions like thymine dimers caused by UV radiation.
- The process involves endonucleases that cut out damaged DNA segments, followed by repair and ligation.(Moderate Yield)
- Deficiency causes xeroderma pigmentosum, leading to: Photosensitivity, Dry skin and ↑ Risk of skin cancers (e.g., melanoma, SCC, BCC)
79. A boy with frequent infections, ataxia, and telangiectasias shows increased AFP and DNA breaks. What gene is defective?
➔ ATM
- Note: Ataxia-telangiectasia results from defective DNA double-strand break repair. Patients are sensitive to radiation and have increased cancer risk.
80. A research lab observes that cells with a DNA repair defect show accumulation of uracil due to cytosine deamination. Which DNA repair mechanism is defective?
➔ Base excision repair
- Note: Spontaneous deamination of cytosine converts it to → uracil, This mutation is removed via the base excision repair pathway using glycosylase, endonuclease, and DNA polymerase/ligase.
- This pathway also fixes spontaneous depurination.
81. A child presents with recurrent infections and is diagnosed with severe combined immunodeficiency (SCID). Labs show buildup of deoxyadenosine in lymphocytes. What enzyme is deficient?
➔ Adenosine deaminase deficiency
- Note: ADA deficiency impairs purine metabolism → accumulation of deoxyadenosine, which is toxic to lymphocytes
- This results in severe combined immunodeficiency (SCID) with ↓ T and B cells
- Other SCID causes:
– RAG gene mutations (defective V(D)J recombination)
– IL-2R deficiency (X-linked SCID)
82. A molecular biologist studying DNA replication notes that a new DNA strand is synthesized continuously in one direction and discontinuously in another. In which direction is DNA synthesized overall?
➔ 5 to 3
- Note: Continuous replication occurs on the leading strand in the 5′→3′ direction, following the replication fork.
- Discontinuous replication occurs on the lagging strand as short Okazaki fragments, synthesized away from the fork and later joined by DNA ligase.
- DNA polymerase III synthesizes new strands 5’→3’. Proofreading (exonuclease activity) occurs in the 3’→5’ direction.
- Primase : Makes RNA primers for the lagging strand. (Moderate Yield)
- DNA polymerase I : Degrades RNA primer with 5′ → 3′ exonuclease. (Moderate Yield)
Created with BioRender.com
83. A 24-year-old man presents to the clinic with dysuria and purulent urethral discharge. He is diagnosed with Neisseria gonorrhoeae infection and is prescribed a fluoroquinolone. These antibiotics exert their effect by interfering with bacterial enzymes that manage DNA supercoiling during replication. Which of the following best describes the mechanism of action of this class of drug?
➔ Inhibits DNA gyrase (topoisomerase II) and topoisomerase IV
- Note: Topoisomerases: cuts one or both DNA strands to relieve tension and prevent supercoiling during replication.
- Prokaryotic(bacterial) topoisomerase = DNA gyrase, inhibited by Fluoroquinolones
- Eukaryotic topoisomerase are targeted in chemotherapy,
○ Topoisomerase I inhibitors = Irinotecan/Topotecan
○ Topoisomerase II inhibitors =Etoposide/teniposide
84. A research team is studying the differences between normal somatic cells and cancer cells. They find that a particular enzyme is upregulated in cancer cells, allowing them to evade replicative senescence and continue dividing. This enzyme most likely functions by?
➔ Adding TTAGGG repeats to the 3’ end of chromosomes
- Note: Telomerase is a reverse transcriptase enzyme that maintains telomere length by adding TTAGGG repeats to the ends of chromosomes.
- Telomerase is more active in germ cells, stem cells, and cancer cells.
- Upregulation in cancer allows cells to divide indefinitely (cellular immortality).
85. During translation, a ribosome encounters the codon 5’-AUG-3’ on an mRNA. Which of the following is the correct corresponding anticodon on the tRNA that will bind this codon?
➔ 3’-UAC-5’
- Note: The anticodon is antiparallel and complementary to the mRNA codon.
- The codon 5’-AUG-3’ is recognized by the anticodon 3’-UAC-5’, which carries methionine (start codon).
- Aminoacyl-tRNA Synthetase charges tRNA by attaching the correct amino acid to the 3′ CCA tail, It ensures accuracy and has proofreading ability.
Created with BioRender.com
86. A molecular biologist is analyzing the interaction between tRNA and mRNA during translation. He notes that a single tRNA molecule can recognize multiple codons that code for the same amino acid. What’s the phenomenon responsible for this ?
➔ Wobble phenomenon
- Note: The wobble phenomenon explains how one tRNA anticodon can pair with multiple mRNA codons for the same amino acid.(Moderate Yield)
- First 2 nucleotides of codon are crucial for anticodon recognition but the 3rd nucleotide can differ
Cell Biology
87. A child with a retinal tumor is found to have a mutation in a gene that normally binds E2F and halts cell cycle progression. What gene is affected?
➔ RB
- Note: The G1 to S phase transition is a critical checkpoint where the cell commits to DNA replication. P53 and Rb work as G1 to S phase checkpoints.
- Rb protein normally inhibits this transition by binding and inactivating E2F, a transcription factor needed for S phase entry. When Rb is phosphorylated, it releases E2F → the cell enters the S phase.
- Rb mutations lead to uncontrolled E2F activation, promoting unregulated cell division = cancers such as osteosarcoma and retinoblastoma.
Created with BioRender.com
88. A 54-year-old woman undergoing chemotherapy develops hair loss. The affected cells in her hair follicles are best classified as which of the following?
➔ Labile
- Note: Labile cells (e.g., hair follicles, gut epithelium, bone marrow) divide rapidly and are most sensitive to chemotherapy.
- Stable cells: Rest in G₀ but can be induced to divide (e.g., hepatocytes)
- Permanent cells: Remain in G₀ and do not divide (e.g., neurons)
89. A researcher inhibits vesicular trafficking from the rough endoplasmic reticulum to the Golgi apparatus. Which protein is most likely affected?
➔ COPII
- Note: COPII is required for anterograde transport from the RER to Golgi. COPI is for retrograde transport from Golgi back to RER.
Signal recognition particle (SRP) guides protein transport cytosol to the RER (Moderate Yield)
90. A chemotherapeutic drug inhibits the polymerization of tubulin dimers into microtubules. Which of the following cellular processes is most likely to be directly impaired by this drug?
➔ Mitotic spindle formation
- Note: Microtubules form the mitotic spindle, essential for separating chromosomes during mitosis and inhibition → stopping cell cycle in M phase.
- Microtubule inhibitors include:Taxanes (hyper stabilize microtubules), Vinca alkaloids, Colchicine, Griseofulvin and Mebendazole.
- Microtubules are also responsible for cellular transport and movement (cilia and flagella).
91. An elderly man presents with a painful vesicular rash in a dermatomal distribution, diagnosed as herpes zoster (shingles). He has a history of chickenpox in childhood and reactivation is suspected.. Which of the following motor proteins is most responsible for this reactivation movement?
➔ Kinesin
- Note: Microtubules are responsible for Axonal transport and movement (cilia and flagella), Retrograde movement = dynein (from axon terminal to Dorsal root ganglion in primary infection).
- Anterograde movement = kinesin (from cell body → axon terminal in reactivation).
- Varicella stays dormant in the dorsal root ganglia and can reactivate causing vesicular skin lesions on a specific dermatome.
Created with BioRender.com
92. 6-year-old boy has a history of recurrent sinus infections, chronic cough, and bronchiectasis. On physical exam, heart sounds are best heard on the right side of the chest. Which of the following is the most likely cause of this patient’s condition?
➔ Defect in dynein arms
- Note: Dynein arms are responsible for the ciliary movement in respiratory epithelium(which is necessary to move secretions and prevent from infections), Dynein arm defects → immotile cilia in primary ciliary dyskinesia (kartagener syndrome)
- The patient presents with : recurrent infection, Bronchiectasis, Situs inversus (Heart on the right on x-ray) and infertility (due to immotile fallopian tube cilia and immotile sperms).
- Note: CF’s infertility is due to bilateral absence of vas deferens.
93. A patient with hyperlipidemia is treated with a statin. This drug inhibits cholesterol synthesis by targeting an enzyme located in which cellular organelle? (Moderate Yield)
➔ Smooth Endoplasmic Reticulum (SER)
- Note: The SER is the site of lipid synthesis, steroid hormone production, and detoxification.
- Statins inhibit HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis, which occurs in the smooth endoplasmic reticulum (SER).
- The Rough Endoplasmic Reticulum (RER) is responsible for protein synthesis.
94. A newborn presents with severe hypotonia and hepatomegaly. Labs show elevated very long-chain fatty acids (VLCFAs). What organelle is defective?
➔ Peroxisome
- Note: Peroxisomes are organelles responsible for β-oxidation of very long-chain fatty acids and metabolism of branched-chain fatty acids and amino acids.
- Zellweger syndrome results from defective peroxisome biogenesis, leading to VLCFA accumulation and neurological impairment.
- Zellweger syndrome, Refsum disease, and adrenoleukodystrophy are all disorders of peroxisomes. (Moderate Yield)
95. A 57-year-old man with advanced colon cancer is started on a targeted therapy that inhibits the ubiquitin-proteasome pathway. Which cellular processes are most likely to be affected by this treatment?
➔ Protein degradation
- Note: Ubiquitin tags proteins for proteasomal degradation.
- The proteasome is responsible for breaking down damaged or regulatory proteins.
- Important for cell cycle regulation, apoptosis, and antigen processing(MHC class I presents endogenous antigens like viral proteins to CD8+ T cells after the proteins are tagged by ubiquitin and degraded by the proteasome).
- Dysfunction is linked to neurodegeneration, cancer, and autoimmune diseases.
Bortezomib is a proteasome inhibitor that blocks degradation of pro-apoptotic proteins by proteasome, leading to cancer cell death, primarily used in multiple myeloma and mantle cell lymphoma.
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GENETICS
96. A father develops Huntington disease at age 50, but his son is diagnosed at age 28 with more severe symptoms. What genetic phenomenon explains this earlier and worsened presentation?
➔ Anticipation
- Note: Seen in trinucleotide repeat disorders (e.g., Huntington [CAG], myotonic dystrophy [CTG], Fragile X [CGG], Friedreich ataxia [GAA]).
- Repeats expand in successive generations, worsening severity and earlier presentation.
97. A 4-year-old girl has café-au-lait spots, fibrous bone lesions, and early-onset puberty. Genetic testing reveals an activating GNAS mutation in some but not all cells. What explains her survival despite this lethal mutation?
➔ Mosaicism
- Note: McCune-Albright syndrome is fatal if all cells carry the mutation.
- Somatic Mosaicism:Mutation occurs after fertilization in somatic (non-germline) cells→ affects parent and not inherited
- Germline (Gonadal) Mosaicism: Mutation is limited to gametes→ affected offspring and parent is normal
98. A family presents for counseling. All affected children show signs of optic atrophy and neurological deficits. The mother is affected, but the father is not. All her children (regardless of sex) are affected. What is the inheritance pattern?
➔ Mitochondrial
- Note: Mitochondrial inheritance comes only from the mother.
- Mitochondrial diseases present with blindness (eye manifestations ) + hearing loss + lactic acidosis + “Ragged red fibers” on biopsy.
- Leber hereditary optic neuropathy (LHON) is a classic example.
99. A 6-year-old girl has progressive muscle weakness, difficulty keeping up with peers, and poor coordination. Genetic testing confirms a mitochondrial disorder. Her mother is asymptomatic, but her older brother has a similar and a more severe presentation. Which of the following best explains the variation in symptom severity among family members?
➔ Heteroplasmy
- Note: Mitochondrial disorders show maternal inheritance and heteroplasmy, which is the presence of both normal and mutated mitochondrial DNA in a cell.
- 1- Pedigree with a diseased mother and all diseased progeny + a diseased father with no diseased progeny = mitochondrial inheritance (only from the mother !)
- 2- Differences in the severity + onset in siblings of a diseased mother are related to the amount of inherited mitochondrial DNA = heteroplasmy
Created with BioRender.com
100. A researcher studies a DNA sequence mutation that silences a tumor suppressor gene by methylation. The affected child has inherited the mutated maternal copy, while the paternal copy is methylated. What genetic phenomenon is this?
➔ Imprinting
- Note: One allele is silenced (imprinted), and the other must be functional.
- If the functional allele is deleted, disease occurs such as following:
○ Prader-Willi (paternal copy deleted)
○ Angelman syndromes (maternal copy deleted).
101. A child with hyperphagia, obesity, and intellectual disability is found to have a deletion on chromosome 15 inherited from the father. What syndrome does this child likely have?
➔ Prader-Willi
- Note: Caused by paternal deletion with maternal imprinting (silencing).
- Prader willi → paternal deletion and maternal imprinting hyperphagia, mental retardation and obesity
- Angel man→ maternal deletion and paternal imprinting mental retardation, laughter, seizures and ataxia
102. A 45-year-old man presents with progressive hair thinning and a family history of similar hair loss. What’s the pattern of inheritance?
➔ Polygenetic
- Note: Androgenic alopecia (male-pattern baldness) is a multifactorial (polygenic) condition, meaning it results from the combined effect of multiple genes and environmental factors.
103. A male child with intellectual disability, a long face, and enlarged testes is found to have CGG trinucleotide expansion affecting the FMR1 gene. What is the mode of inheritance of this condition?
➔ X-dominant
- Note: Fragile X syndrome is X-linked dominant with CGG trinucleotide repeats (resulting in methylation and silencing) and can present with anticipation.
- Associated with autism, MVP, and joint laxity.
- Other presentations include large jaw, everted ears and self mutilation (confused with lesch nyhan syndrome).
104. A healthy child, but his brother has Kartagener syndrome. What is the probability that this child is a carrier?
➔ 2/3
- Note: For autosomal recessive disorders, if one sibling is affected, the chance a healthy sibling is a carrier is 2/3.
| A (from Parent 2) | a (from Parent 2) | |
|---|---|---|
| A (Parent 1) | AA (Unaffected, not a carrier) | Aa (Carrier) |
| a (Parent 1) | Aa (Carrier) | aa (Affected) |
105. A 32-year-old normal woman with a brother affected by an autosomal recessive metabolic disorder presents for preconception counseling. Her partner is unrelated and has no family history of the disease. The disease prevalence in the general population is 1 in 10,000. What is the probability that their child will be affected by the disease?
➔ 1 in 300
- Note: Always do it in 4 systematic steps:
1- calculate the risk of the mother being a carrier
She is not diseased so = could be normal or a carrier and according to the 2*2 table:
| A (from Parent 2) | a (from Parent 2) | |
|---|---|---|
| A (Parent 1) | AA (Unaffected, not a carrier) | Aa (Carrier) |
| a (Parent 1) | Aa (Carrier) | aa (Affected) |
She has a ⅔ probability of being a carrier.
2- Calculate the mother’s probability of passing the diseased allele = ½
3- Calculate the father’s risk of being a carrier :
p² =1/10000
p= 1/100 and q= 1 – (1/100) = 99/100 ≈ 1
Then the carrier risk is:
2pq = 2 × (1/100) × (99/100) = 1/50
4- Calculate the father’s risk of passing the abnormal copy = ½
Then multiply all four : ⅔ × ½ × 1/50 × ½ = 1/300
106. If 9% of a population is homozygous for an autosomal dominant trait, what percentage of the population is heterozygous?
➔ 42%
- Note: For a dominant trait,
p² = 0.09 → p = 0.3.
Thus, q = 1 – 0.3 = 0.7.
The heterozygous frequency (2pq) is 2 × 0.3 × 0.7 = 0.42 (42%).
107. A 14-year-old boy presents with a cough and recurrent lung infections. He also has steatorrhea and azoospermia. Sweat chloride is elevated. What finding is likely found on autopsy?
➔ Bilateral absence of Vas deferens
- Note: Cystic fibrosis is autosomal recessive and causes congenital absence of vas deferens (kartagener syndrome has a similar presentation with infertility caused by less sperm motility).
- The CFTR is misfolded and accumulates in the RER(not secreted into the cell membrane)
108. A 6-year-old boy is brought to the physician because of recurrent respiratory infections. A sweat chloride test is markedly elevated. Which of the following best describes the mechanism responsible for high chloride levels in this patient’s sweat?
➔ Impaired chloride reabsorption and decreased ENaC activity
- Note: In sweat glands, CFTR normally reabsorbs Cl⁻ and also stimulates ENaC to reabsorb Na⁺.
- In cystic fibrosis, defective CFTR leads to less Cl⁻ and Na⁺ reabsorption, so sweat becomes saltier (↑ Na⁺ and Cl⁻).
- In contrast, in the lungs and GI tract, CFTR normally secretes Cl⁻ into the lumen and inhibits ENaC, keeping the mucus hydrated. In CF, defective CFTR means less Cl⁻ secretion and more Na⁺ reabsorption via ENaC, leading to dry, thick mucus due to water following sodium out of the lumen.
Created with BioRender.com
109. A 6-month-old boy presents with recurrent respiratory infections, failure to thrive, and steatorrhea. Sweat chloride testing is positive. What is the genetic defect?
➔ CFTR
- Note: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutation on chromosome 7, most commonly ΔF508. (Moderate Yield)
- Leads to defective chloride and water transport, causing thick mucus in lungs and GI tract → more lung infections, pancreatic insufficiency, fat soluble vitamin deficiency (A,D,E,K) and meconium ileus in newborn.
110. A boy presents with calf hypertrophy and uses his arms to rise from the floor. His uncle died of heart failure at age 19. What is the likely mutation type?
➔ Frameshift
- Note: Duchenne muscular dystrophy cause: pelvic girdle muscle weakness (weakness starts proximal not distal) with ↑CPK due to muscle breakdown, Calf pseudohypertrophy (muscle replaced by fat and connective tissue),Gowers sign (uses his arm to rise) and can lead to dilated cardiomyopathy.
- Duchenne muscular dystrophy is caused by frameshift or nonsense mutations while Becker results from non frameshift mutation(less severe with a partially functional gene).
111. A man has trouble releasing his grip after a handshake. He also has cataracts, early balding, and arrhythmias. What is the inheritance pattern?
➔ Autosomal Dominant
- Note: Myotonic dystrophy is autosomal dominant with CTG repeat expansion affecting the DMPK gene.
- Myotonia (trouble releasing his grip)
112. A 10-year-old boy is brought to the physician because of recent-onset headaches and vision changes. Physical examination shows multiple café-au-lait macules and axillary freckling. MRI reveals an optic glioma. His father has similar skin findings but no neurologic symptoms. Which of the following best explains the difference in clinical presentation between the patient and his father?
➔ Variable expressivity
- Note: Neurofibromatosis type I is an autosomal dominant disorder with complete penetrance but variable expressivity = all individuals with the mutation show some symptoms, but the severity varies.
- One person may have only skin findings while another has CNS tumors.
- Heteroplasmy has a similar presentation exclusively for the mitochondrial disorders (leber hereditary optic neuropathy)
113. A child with intellectual disability, flat facies, single palmar crease, and hypotonia is born to a 44-year-old mother. What is the most likely mechanism?
➔ Nondisjunction
- Note: Trisomy 21 (Down syndrome) is most commonly due to meiotic nondisjunction. Risk increases with maternal age.
- GI: Duodenal atresia, Hirschsprung disease
- Neuro: Intellectual disability, early-onset Alzheimer’s
- Cardiac: Atrioventricular septal defects (e.g., endocardial cushion defects).
Increased AML, ALL and type 1 DM risk and high B-HCG /inhibin A in 2nd trimester screening
- Other HY causes of down syndrome:
– Robertsonian translocation (familial Down )
– Mosaicism (~1%)
114. A 6-month-old boy is diagnosed with Down syndrome. Karyotyping reveals 46 chromosomes, with a translocation involving chromosomes 14 and 21. Which of the following best describes the genetic mechanism responsible for this patient’s condition?
➔ Robertsonian translocation
- Note: Acrocentric chromosomes have the centromere near one end, creating a very short (p) arm and a long (q) arm. (Moderate Yield)
- Robertsonian translocation: Long arm of chromosome 21 is attached to another acrocentric chromosome (commonly chromosome 14), leading to extra 21q material. (Moderate Yield)
- Patient has 46 chromosomes, but trisomy 21 phenotype due to functional gene dosage increase.
- Often inherited, especially in familial Down syndrome.
Created with BioRender.com
115. A 2-month-old infant with clenched fists, rocker-bottom feet, and micrognathia dies from a congenital heart defect. What karyotype is expected? (Moderate Yield)
➔ Trisomy 18
- Note: Edwards syndrome. Death usually occurs by age 1. Also features low-set ears, prominent occiput and omphalocele. Also shows low HCG in the 2nd trimester screening.
116. A newborn with severe intellectual disability, polydactyly, cleft lip, and holoprosencephaly is found to have a congenital heart defect. What is the most likely diagnosis?
➔ Patau syndrome
- Note: Trisomy 13 associated with cleft lip/palate, holoprosencephaly, polycystic kidneys and polydactyly. Very poor prognosis. Also shows low HCG on 2nd trimester screening.
117. A girl with short stature, webbed neck, and widely spaced nipples is found to have streak ovaries and primary amenorrhea. What hormone level is elevated?
➔ FSH
- Note: Turner syndrome (45,X0) has ovarian dysgenesis → ↓ estrogen → ↑ FSH/LH. Also associated with bicuspid aortic valve and coarctation of the aorta.
118. A newborn with cleft palate, hypocalcemia, and congenital heart disease is found to have DiGeorge syndrome. Which of the following best describes the genetic mechanism underlying this condition?
➔ Microdeletion at 22q11.2
- Note: The 3rd pharyngeal pouch forms the inferior parathyroid glands and thymus.
- The 4th pharyngeal pouch gives rise to the superior parathyroid glands
- DiGeorge syndrome is caused by a microdeletion at 22q11.2, affecting development of the 3rd and 4th pharyngeal pouches.
- This leads to thymic and parathyroid hypoplasia → hypocalcemia and T cell immunodeficiency and conotruncal heart defects.
🏁 Final Thoughts
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Disclaimer
Version 1.0 May 2025. No part of this document may be reproduced or distributed without written permission. For personal study only. Medical information herein is for educational purposes and does not constitute clinical advice. Always confirm with current guidelines and your institution’s policies.
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