I have my mbbs final exam and it’s going to be an mcq exam I want you to creat 100 questions from the topics make sure they are theoretical as well as clinically based questions take reference from Biochemistry with clinical correlations; Thomas M. Devlin, 7th edition Beta Oxidation; Carnitine Shuttle; alpha and omega oxidation; Refsum Disease Synthesis of Fatty Acids, Triacylglycerols, and the Major Membrane Lipids; Regulation of Lipogenesis. Cholesterol Absorption, Synthesis, Metabolism, and Fate; Ketone Bodies; Ketogenesis; Regulation of Cholesterol synthesis and ketogenesis Integration of Carbohydrate and Lipid Metabolism; Feed Starve Cycle; Diabetes, Classification, Biochemical aspects of diabetes Urea Cycle; Negative and positive nitrogen balance; Transamination and deamination reactions; Regulation of urea cycle. Hormones: classification, mechanism of action. Hormones; Thyroid hormones; Adrenal hormones

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Here are your 100 MBBS Final MCQs, organized by topic, with answers and explanations at the end.

100 MCQs - Biochemistry (MBBS Final)

Reference: Devlin's Biochemistry with Clinical Correlations, 7th Ed. (+ Lippincott, Harper's, Basic Medical Biochemistry)

SECTION 1: Beta Oxidation, Carnitine Shuttle, Alpha and Omega Oxidation, Refsum Disease

(Questions 1-15)

Q1. Which of the following correctly describes the sequence of reactions in one round of mitochondrial beta-oxidation?

A) Reduction → Hydration → Oxidation → Thiolysis B) Oxidation → Hydration → Oxidation → Thiolysis C) Dehydration → Oxidation → Reduction → Thiolysis D) Hydration → Oxidation → Hydration → Thiolysis

Q2. The carnitine shuttle is required for:

A) Transfer of acetyl CoA from mitochondria to cytoplasm B) Transfer of long-chain fatty acyl CoA from cytoplasm into the mitochondrial matrix C) Transfer of short-chain fatty acids across the outer mitochondrial membrane D) Transfer of NADH from cytoplasm into mitochondria

Q3. A 3-year-old child is brought with muscle weakness, hypoglycemia, and non-ketotic dicarboxylic aciduria. Urine organic acid analysis shows elevated C8-C10 acylcarnitines. Which enzyme deficiency is most likely?

A) Long-chain acyl CoA dehydrogenase (LCAD) B) Medium-chain acyl CoA dehydrogenase (MCAD) C) Short-chain acyl CoA dehydrogenase (SCAD) D) Carnitine palmitoyltransferase I (CPT-I)

Q4. The net ATP yield from the complete oxidation of one molecule of palmitic acid (C16:0) is:

A) 96 ATP B) 106 ATP C) 129 ATP D) 80 ATP

Q5. In beta-oxidation of an unsaturated fatty acid such as oleic acid (C18:1, Δ9), which additional enzyme is required?

A) An isomerase (enoyl-CoA isomerase) B) A reductase using NADPH C) Both isomerase and reductase D) No additional enzymes

Q6. Omega (ω)-oxidation of fatty acids occurs in which cellular compartment?

A) Mitochondrial matrix B) Peroxisomes C) Endoplasmic reticulum (microsomes) D) Cytosol

Q7. Omega-oxidation converts a fatty acid to a dicarboxylic acid. The first step involves oxidation of the omega-carbon by:

A) Cytochrome P450 (CYP4A) using NADPH and O2 B) Acyl CoA oxidase using FAD C) Carnitine acyltransferase D) Thiolase

Q8. A patient presents with peripheral neuropathy, cerebellar ataxia, retinitis pigmentosa, and elevated plasma phytanic acid. This is consistent with:

A) Zellweger syndrome B) Refsum disease C) MCAD deficiency D) Abetalipoproteinemia

Q9. Refsum disease results from deficiency of which enzyme?

A) Phytanoyl-CoA alpha-hydroxylase (PHYH) B) Pristanoyl-CoA alpha-hydroxylase C) Very-long-chain acyl-CoA synthetase D) Carnitine palmitoyltransferase II

Q10. In alpha-oxidation, phytanic acid is converted to:

A) Pristanic acid + CO2 B) Pristanic acid + H2O2 C) Phytol + CO2 D) Propionyl CoA + CO2

Q11. Primary carnitine deficiency (systemic carnitine deficiency) is due to a defect in:

A) CPT-I B) CPT-II C) The plasma membrane carnitine transporter (OCTN2) D) Carnitine-acylcarnitine translocase

Q12. Peroxisomal beta-oxidation differs from mitochondrial beta-oxidation in that:

A) The first step uses FAD-linked oxidase that generates H2O2 instead of FADH2 B) NADPH is the electron acceptor in the first oxidation step C) Peroxisomes cannot oxidize very-long-chain fatty acids D) Carnitine is required for fatty acid entry into peroxisomes

Q13. During prolonged fasting, the predominant fuel for skeletal muscle is:

A) Glucose B) Ketone bodies only C) Free fatty acids (via beta-oxidation) D) Lactate

Q14. A 4-month-old infant dies suddenly. Autopsy shows microvesicular hepatic steatosis. Postmortem metabolic studies suggest a fatty acid oxidation defect. The most common inborn error in this category is:

A) LCHAD deficiency B) MCAD deficiency C) CPT-II deficiency D) VLCAD deficiency

Q15. The ketone bodies acetoacetate and beta-hydroxybutyrate cannot be utilized by:

A) Cardiac muscle B) Skeletal muscle C) Brain (during starvation) D) Liver

SECTION 2: Fatty Acid Synthesis, Triacylglycerol Synthesis, Major Membrane Lipids, Regulation of Lipogenesis

(Questions 16-28)

Q16. The committed step in fatty acid synthesis is catalyzed by:

A) Fatty acid synthase (FAS) B) Acetyl CoA carboxylase (ACC) C) ATP-citrate lyase D) Malonyl CoA-ACP transacylase

Q17. Acetyl CoA carboxylase (ACC) is allosterically activated by:

A) Palmitoyl CoA B) Glucagon C) AMP-activated protein kinase (AMPK) D) Citrate

Q18. The elongation of fatty acids beyond C16 palmitic acid in the endoplasmic reticulum uses which activated 2-carbon donor?

A) Acetyl CoA B) Malonyl CoA C) Acetoacetyl CoA D) Succinyl CoA

Q19. Fatty acid synthesis occurs in the:

A) Mitochondrial matrix B) Peroxisomes C) Cytoplasm (cytosol) D) Smooth endoplasmic reticulum

Q20. The rate-limiting step in triacylglycerol (TAG) synthesis is:

A) Formation of glycerol-3-phosphate B) Phosphatidate phosphatase (lipin) reaction C) DAG acyltransferase (DGAT) reaction D) CDP-diacylglycerol formation

Q21. Phosphatidylcholine (lecithin) synthesis by the CDP-choline pathway requires which rate-limiting enzyme?

A) Choline kinase B) CTP:phosphocholine cytidylyltransferase (CCT) C) Phospholipase A2 D) Cholinephosphotransferase

Q22. A patient with morbid obesity undergoes bariatric surgery. Postoperatively, she requires carnitine supplementation. Which of the following best explains the biochemical basis?

A) Carnitine is needed for glucose entry into mitochondria B) Carnitine is required for transport of long-chain fatty acyl CoA into mitochondria for beta-oxidation C) Carnitine is a cofactor for acetyl CoA carboxylase D) Carnitine stimulates malonyl CoA synthesis

Q23. Malonyl CoA inhibits which enzyme, thereby coupling fatty acid synthesis and oxidation?

A) Acetyl CoA carboxylase B) Carnitine palmitoyltransferase I (CPT-I) C) Fatty acid synthase D) HMG-CoA reductase

Q24. The primary source of NADPH for fatty acid synthesis in the liver is:

A) Malate dehydrogenase reaction B) Isocitrate dehydrogenase in TCA cycle C) Pentose phosphate pathway (HMP shunt) D) Glycolysis

Q25. Sphingomyelin is synthesized from:

A) Ceramide + CDP-choline B) Ceramide + Phosphatidylcholine C) Sphingosine + UDP-glucose D) Serine + Palmitoyl CoA (as initial step, then ceramide + phosphatidylcholine)

Q26. The principal lipid component of pulmonary surfactant is:

A) Phosphatidylinositol B) Dipalmitoylphosphatidylcholine (DPPC) C) Cardiolipin D) Sphingomyelin

Q27. Insulin stimulates lipogenesis by:

A) Inhibiting phosphodiesterase, raising cAMP B) Activating AMPK C) Dephosphorylating and activating ACC; upregulating FAS gene expression via SREBP-1c D) Activating hormone-sensitive lipase

Q28. In a patient with insulin resistance and type 2 diabetes, elevated plasma free fatty acids feed back to the liver. This leads to increased synthesis of:

A) HDL-cholesterol B) VLDL-triacylglycerols C) Chylomicrons D) LDL particles only

SECTION 3: Cholesterol Synthesis, Metabolism, Fate, Ketone Bodies, Ketogenesis, and Regulation

(Questions 29-44)

Q29. The rate-limiting step of cholesterol biosynthesis is:

A) Farnesyl pyrophosphate → Squalene (squalene synthase) B) HMG-CoA → Mevalonate (HMG-CoA reductase) C) Mevalonate → Mevalonate-5-phosphate D) Squalene → Lanosterol (squalene monooxygenase)

Q30. All 27 carbons of cholesterol are derived from:

A) Glucose via glycolysis B) Acetyl CoA C) Acetoacetyl CoA only D) Malonyl CoA

Q31. Statins (HMG-CoA reductase inhibitors) lower LDL-cholesterol by:

A) Directly blocking LDL receptor internalization B) Reducing hepatic cholesterol → upregulating LDL receptors → increased clearance of LDL from plasma C) Activating ACAT to store more cholesterol as esters D) Inhibiting PCSK9

Q32. Bile acids are synthesized from cholesterol. The rate-limiting enzyme in this pathway is:

A) 7-alpha-hydroxylase (CYP7A1) B) 12-alpha-hydroxylase C) Steroid 27-hydroxylase D) HMG-CoA reductase

Q33. A 45-year-old man has xanthomas, premature coronary artery disease, and LDL >400 mg/dL despite moderate diet. His father died of MI at age 40. The most likely diagnosis is:

A) Familial combined hyperlipidemia B) Familial hypercholesterolemia (FH) - homozygous C) Familial hypercholesterolemia (FH) - heterozygous D) Sitosterolemia

Q34. Which lipoprotein is primarily responsible for reverse cholesterol transport?

A) VLDL B) IDL C) LDL D) HDL

Q35. In the liver, cholesterol balance is maintained by SCAP-SREBP pathway. When intracellular cholesterol is HIGH, what happens?

A) SCAP escorts SREBP-2 to Golgi → active SREBP is released → LDL receptor gene is upregulated B) Insigs retain SCAP-SREBP in the ER → SREBP-2 is not cleaved → LDL receptor gene is NOT upregulated C) ACAT is inhibited → free cholesterol accumulates D) CYP7A1 is inhibited → bile acid synthesis decreases

Q36. Ketone body synthesis (ketogenesis) occurs in:

A) Hepatic cytoplasm B) Hepatic mitochondria C) Extrahepatic tissues D) Adipocytes

Q37. The key enzyme unique to hepatic ketogenesis is:

A) Thiolase B) Acetoacetyl CoA thiolase C) HMG-CoA synthase (mitochondrial) D) HMG-CoA reductase

Q38. A 16-year-old girl with type 1 diabetes presents with nausea, vomiting, fruity breath, rapid deep breathing (Kussmaul respirations), and blood glucose of 480 mg/dL. Serum bicarbonate is 8 mEq/L. What is the predominant fuel being metabolized by her liver at this time?

A) Glucose B) Amino acids C) Fatty acids (with ketone body formation) D) Lactate

Q39. The ratio of beta-hydroxybutyrate to acetoacetate in blood under normal fed conditions is approximately:

A) 1:1 B) 1:3 C) 3:1 D) 10:1

Q40. Acetone (one of the ketone bodies) is formed by:

A) Enzymatic reduction of acetoacetate by beta-hydroxybutyrate dehydrogenase B) Spontaneous non-enzymatic decarboxylation of acetoacetate C) Enzymatic oxidation of beta-hydroxybutyrate D) HMG-CoA lyase reaction

Q41. Which of the following is NOT a ketone body?

A) Acetoacetate B) Beta-hydroxybutyrate C) Acetone D) Acetyl CoA

Q42. Ketone body utilization in peripheral tissues requires which enzyme that is absent in the liver?

A) Beta-hydroxybutyrate dehydrogenase B) Succinyl CoA-acetoacetate CoA transferase (succinyl CoA transferase / thiophorase) C) Acetoacetyl CoA thiolase D) HMG-CoA synthase

Q43. Regulation of HMG-CoA reductase includes all of the following EXCEPT:

A) Insulin activates it (via dephosphorylation) B) Glucagon inhibits it (via phosphorylation by PKA) C) It undergoes feedback inhibition by mevalonate D) Statins competitively inhibit it

Q44. A malnourished child has low serum albumin, edema, and high urinary ketones. Which metabolic adaptation is reflected by the high urinary ketones?

A) Increased glucose utilization B) Increased fatty acid mobilization and hepatic ketogenesis due to low insulin C) Increased glycogenolysis D) Increased gluconeogenesis from protein only

SECTION 4: Integration of Carbohydrate and Lipid Metabolism - Feed-Starve Cycle

(Questions 45-55)

Q45. During the absorptive (fed) state, the liver primarily:

A) Produces glucose via gluconeogenesis B) Exports fatty acids as VLDL-TAG and converts excess glucose to glycogen and lipids C) Releases ketone bodies D) Mobilizes glycogen only

Q46. In the post-absorptive (fasting) state after approximately 8-12 hours, which is the PRIMARY fuel for the brain?

A) Fatty acids B) Ketone bodies C) Glucose (from glycogenolysis and gluconeogenesis) D) Amino acids

Q47. Which hormone most directly opposes insulin's lipogenic and glycogen-synthetic actions?

A) Epinephrine B) Cortisol C) Glucagon D) Growth hormone

Q48. During prolonged starvation (>5 days), the brain adapts by using:

A) Exclusively glucose B) Fatty acids as the primary fuel C) Ketone bodies for up to 70% of its energy needs D) Alanine via gluconeogenesis

Q49. The Randle cycle (glucose-fatty acid cycle) describes:

A) Reciprocal relationship between fatty acid oxidation and glucose utilization in tissues B) Cycling of glucose between liver and muscle C) The relationship between cholesterol and glucose synthesis D) Interaction of insulin and glucagon

Q50. Substrate cycling (futile cycling) between fructose-6-phosphate and fructose-1,6-bisphosphate involves which pair of enzymes?

A) Glucokinase and glucose-6-phosphatase B) Phosphofructokinase-1 (PFK-1) and fructose-1,6-bisphosphatase (FBPase-1) C) Pyruvate kinase and pyruvate carboxylase D) PFK-2 and FBPase-2

Q51. In the liver during fasting, elevated glucagon:cAMP ratio leads to all of the following EXCEPT:

A) Activation of glycogen phosphorylase B) Inhibition of glycogen synthase C) Activation of pyruvate kinase D) Activation of hormone-sensitive lipase in adipose

Q52. The carbon skeletons of glucogenic amino acids enter the TCA cycle at which point to support gluconeogenesis?

A) Acetyl CoA B) As OAA, alpha-ketoglutarate, succinyl CoA, fumarate, or pyruvate C) Only as pyruvate D) As acetoacetate

Q53. Alanine released from muscle during fasting undergoes which process in the liver?

A) Direct incorporation into protein B) Transamination to pyruvate → gluconeogenesis (glucose-alanine cycle) C) Conversion to fatty acids D) Oxidation via TCA cycle only

Q54. Which of the following is the main allosteric activator of pyruvate carboxylase, the first step of gluconeogenesis from pyruvate?

A) ADP B) Acetyl CoA C) AMP D) Malonyl CoA

Q55. During exercise, muscle uses glycogen and fatty acids. The metabolite that directly inhibits CPT-I and reduces fatty acid oxidation in the fed state is:

A) Citrate B) Malonyl CoA C) NADH D) ATP

SECTION 5: Diabetes - Classification and Biochemical Aspects

(Questions 56-67)

Q56. Type 1 diabetes mellitus is characterized by:

A) Peripheral insulin resistance with relative insulin deficiency B) Autoimmune destruction of pancreatic beta cells leading to absolute insulin deficiency C) Defective insulin receptors D) Increased hepatic insulin clearance

Q57. The pathognomonic biochemical triad of diabetic ketoacidosis (DKA) is:

A) Hyperglycemia, ketonemia/ketonuria, metabolic alkalosis B) Hyperglycemia, ketonemia/ketonuria, high-anion-gap metabolic acidosis C) Hypoglycemia, hyperketonemia, metabolic acidosis D) Hyperglycemia, lactic acidosis, absence of ketones

Q58. HbA1c reflects average blood glucose over:

A) 1-2 weeks B) 2-4 weeks C) 8-12 weeks (approximately 3 months) D) 6 months

Q59. In type 2 diabetes, the earliest detectable defect is usually:

A) Absolute insulin deficiency B) Peripheral insulin resistance (in muscle and adipose) C) Loss of all pancreatic islet cells D) Autoantibodies to insulin receptor

Q60. Glucose enters hepatocytes and pancreatic beta cells via which transporter?

A) GLUT-1 B) GLUT-2 (high Km, high capacity) C) GLUT-4 (insulin-dependent) D) GLUT-3

Q61. In a patient with uncontrolled type 1 diabetes, why does hyperglycemia persist despite cellular glucose deficiency?

A) Excess glucokinase activity B) Absence of insulin prevents GLUT-4 translocation to cell membrane in muscle and adipose → decreased glucose uptake; simultaneously, glucagon promotes gluconeogenesis and glycogenolysis C) Excess insulin receptor downregulation D) Increased glycolysis consumes all glucose

Q62. Non-enzymatic glycation of proteins in diabetes leads to advanced glycation end products (AGEs). These primarily contribute to:

A) Hypoglycemia B) Microvascular complications (retinopathy, nephropathy, neuropathy) C) Increased LDL clearance D) Enhanced insulin secretion

Q63. The polyol pathway (sorbitol pathway) is activated in hyperglycemia. The enzyme that initiates this pathway is:

A) Phosphoglucoisomerase B) Aldose reductase C) Sorbitol dehydrogenase D) Glucokinase

Q64. Maturity-onset diabetes of the young (MODY) type 2 is caused by mutations in:

A) Insulin receptor gene B) Glucokinase gene (GCK) C) HNF-1-alpha gene D) ABCC8 (sulfonylurea receptor gene)

Q65. A patient with type 1 DM presents with confusion and diaphoresis. Blood glucose is 38 mg/dL. This hypoglycemia is most likely due to:

A) Excess glucagon secretion B) Excess exogenous insulin administration C) Renal glucose wasting D) Increased peripheral glucose uptake by GLUT-2

Q66. In type 2 diabetes, metformin acts primarily by:

A) Stimulating insulin secretion from beta cells B) Activating AMPK → inhibiting hepatic gluconeogenesis C) Blocking intestinal glucose absorption only D) Activating PPAR-gamma in adipose tissue

Q67. Diabetic ketoacidosis is more common in type 1 DM because:

A) Type 1 patients are older and more obese B) Absolute insulin deficiency allows unopposed glucagon action → maximal lipolysis and hepatic ketogenesis C) Type 1 patients have more dysfunctional LDL receptors D) Type 2 DM produces excess ketones via protein catabolism

SECTION 6: Urea Cycle, Nitrogen Balance, Transamination, Deamination, Regulation

(Questions 68-78)

Q68. The urea cycle is located in which tissue?

A) Kidney B) Skeletal muscle C) Liver (hepatocytes) D) Intestinal epithelium

Q69. The first two reactions of the urea cycle occur in the:

A) Cytoplasm B) Mitochondrial matrix C) Smooth endoplasmic reticulum D) Peroxisome

Q70. The two nitrogen atoms in urea are derived from:

A) Two molecules of glutamate B) NH4+ (free ammonia) and aspartate C) Glutamine and alanine D) Ammonia and glutamine

Q71. N-acetylglutamate (NAG) is an allosteric activator of which urea cycle enzyme?

A) Ornithine transcarbamylase (OTC) B) Argininosuccinate synthetase C) Carbamoyl phosphate synthetase I (CPS-I) D) Arginase

Q72. A 2-day-old neonate presents with lethargy, vomiting, and seizures after protein feeding. Blood ammonia is markedly elevated. Plasma citrulline is undetectable. Which enzyme deficiency is most likely?

A) Arginase deficiency B) Argininosuccinate lyase deficiency C) Carbamoyl phosphate synthetase I deficiency D) Ornithine transcarbamylase (OTC) deficiency

Q73. The reaction catalyzed by alanine aminotransferase (ALT) is:

A) Alanine + alpha-ketoglutarate → Pyruvate + Glutamate B) Alanine + oxaloacetate → Pyruvate + Aspartate C) Alanine + NAD+ → Pyruvate + NH4+ D) Alanine + ATP → Alanyl-AMP + PPi

Q74. Pyridoxal phosphate (PLP), derived from Vitamin B6, is required as a cofactor for:

A) Oxidative deamination by glutamate dehydrogenase B) All transaminase (aminotransferase) reactions C) Urea synthesis by arginase D) Carbamoyl phosphate synthesis

Q75. Glutamate dehydrogenase catalyzes oxidative deamination of glutamate. This reaction is allosterically activated by:

A) GTP and ATP B) ADP and leucine C) NAD+ only D) NADPH

Q76. Positive nitrogen balance is seen in which of the following states?

A) Burns and sepsis B) Prolonged starvation C) Pregnancy, growth, recovery from illness D) Cushing syndrome

Q77. Which of the following is the predominant form in which nitrogen is transported from peripheral tissues to the liver?

A) Free ammonia B) Urea C) Alanine and glutamine D) Aspartate

Q78. Hyperammonemia causes neurological symptoms primarily because ammonia:

A) Directly destroys neurons B) Depletes alpha-ketoglutarate (OAA) from TCA cycle by forming glutamate/glutamine → impairs energy production and causes brain swelling (cerebral edema) C) Crosses the blood-brain barrier and causes direct acidosis D) Inhibits synaptic dopamine reuptake

SECTION 7: Hormones - Classification and Mechanism of Action

(Questions 79-86)

Q79. Hormones that act via intracellular (nuclear) receptors include:

A) Insulin and glucagon B) Epinephrine and norepinephrine C) Thyroid hormones (T3, T4) and steroid hormones D) Growth hormone and prolactin

Q80. The second messenger for glucagon and epinephrine (beta-adrenergic) action is:

A) Inositol triphosphate (IP3) B) Cyclic AMP (cAMP) C) Cyclic GMP (cGMP) D) Diacylglycerol (DAG)

Q81. The action of insulin involves:

A) Activation of adenylyl cyclase → increase in cAMP B) Activation of a receptor tyrosine kinase → phosphorylation of IRS-1 → activation of PI3K/Akt pathway C) Binding to a nuclear receptor → gene transcription D) Activation of phospholipase C → IP3 and DAG

Q82. Nitric oxide (NO) stimulates which enzyme to increase cGMP?

A) Adenylyl cyclase B) Phosphodiesterase C) Soluble guanylyl cyclase D) Protein kinase A

Q83. Which class of hormones requires a "G-protein coupled receptor" (GPCR) as the primary membrane receptor?

A) Insulin and IGF-1 B) Glucocorticoids C) Glucagon, epinephrine (beta), TSH, LH, FSH, PTH D) Thyroid hormones

Q84. A patient is prescribed sildenafil (Viagra). It acts by inhibiting PDE-5, leading to accumulation of cGMP in vascular smooth muscle. This is an example of pharmacological manipulation of which signaling pathway?

A) Receptor tyrosine kinase pathway B) JAK-STAT pathway C) Nitric oxide-cGMP signaling pathway D) Phospholipase C pathway

Q85. Steroid hormones exert their effects via:

A) Cell surface GPCRs only B) Intracellular receptors that act as transcription factors in the nucleus C) Receptor-linked kinases D) Second messengers like cAMP

Q86. Hormones that act via the JAK-STAT pathway include:

A) Cortisol and aldosterone B) Growth hormone, prolactin, erythropoietin, cytokines (e.g., interferon) C) Insulin and IGF-1 D) Glucagon and PTH

SECTION 8: Thyroid Hormones and Adrenal Hormones

(Questions 87-100)

Q87. Thyroid hormones (T3 and T4) are synthesized from which amino acid?

A) Tryptophan B) Phenylalanine C) Tyrosine D) Histidine

Q88. The enzyme responsible for organification of iodide and coupling of iodotyrosines is:

A) Deiodinase B) Thyroid peroxidase (TPO) C) Thyroglobulin protease D) Iodide permease (NIS)

Q89. Which of the following thyroid hormone preparations is the most biologically active at the cellular level?

A) T4 (thyroxine) B) T3 (triiodothyronine) C) Reverse T3 (rT3) D) MIT (monoiodotyrosine)

Q90. A 35-year-old woman presents with weight loss, heat intolerance, palpitations, tremor, and exophthalmos. TSH is undetectable and free T4 is elevated. The most likely diagnosis is:

A) Hashimoto thyroiditis B) Graves disease (autoimmune hyperthyroidism) C) Thyroid cancer D) De Quervain thyroiditis

Q91. Propylthiouracil (PTU) reduces thyroid hormone levels by which mechanism?

A) Blocking TSH receptors B) Inhibiting thyroid peroxidase AND inhibiting peripheral conversion of T4 to T3 by deiodinase C) Blocking iodide uptake by NIS D) Accelerating hepatic conjugation of T4

Q92. The biochemical effects of thyroid hormones on metabolism include:

A) Decreased basal metabolic rate (BMR) B) Increased BMR; upregulation of Na+/K+-ATPase; increased cholesterol synthesis and degradation (net decrease in LDL) C) Decreased protein synthesis D) Inhibition of glucose absorption from intestine

Q93. The adrenal cortex is divided into three zones. Aldosterone is produced by the:

A) Zona fasciculata B) Zona reticularis C) Zona glomerulosa D) Adrenal medulla

Q94. Cortisol (glucocorticoid) exerts which of the following metabolic effects?

A) Promotes glycogen synthesis; inhibits gluconeogenesis B) Promotes gluconeogenesis (via upregulation of PEPCK); promotes protein catabolism in muscle; promotes lipolysis; has anti-inflammatory effects C) Reduces blood glucose D) Stimulates insulin secretion

Q95. A 40-year-old woman presents with central obesity, moon facies, buffalo hump, purple striae, hypertension, hyperglycemia, and easy bruising. 24-hour urinary free cortisol is markedly elevated. The diagnosis is:

A) Addison disease B) Conn syndrome (primary hyperaldosteronism) C) Cushing syndrome D) Pheochromocytoma

Q96. Primary adrenal insufficiency (Addison disease) is characterized biochemically by:

A) Elevated cortisol, low ACTH B) Low cortisol, low aldosterone, HIGH ACTH (due to loss of negative feedback) C) High aldosterone, low renin D) Low ACTH and low cortisol due to hypothalamic failure

Q97. Congenital adrenal hyperplasia (CAH) most commonly results from deficiency of:

A) 11-beta-hydroxylase B) 21-alpha-hydroxylase (CYP21A2) C) 17-alpha-hydroxylase D) 3-beta-hydroxysteroid dehydrogenase

Q98. Catecholamines (epinephrine, norepinephrine) are synthesized in the adrenal medulla from:

A) Phenylalanine → Tyrosine → DOPA → Dopamine → Norepinephrine → Epinephrine B) Tryptophan → Serotonin → Melatonin C) Histidine → Histamine D) Arginine → Nitric oxide

Q99. A 30-year-old man presents with episodic hypertension, headache, sweating, and palpitations. Urine metanephrines are markedly elevated. Which adrenal tumor is most likely?

A) Adrenocortical carcinoma B) Aldosteronoma (Conn tumor) C) Pheochromocytoma D) Neuroblastoma

Q100. Aldosterone acts on the distal convoluted tubule and collecting duct to:

A) Decrease Na+ reabsorption and increase K+ retention B) Increase Na+ reabsorption and increase K+ excretion by inducing synthesis of ENaC and Na+/K+-ATPase C) Promote water excretion (diuresis) D) Increase H+ reabsorption

ANSWER KEY WITH EXPLANATIONS

1. B - Beta-oxidation sequence: Oxidation (by acyl-CoA dehydrogenase, produces FADH2) → Hydration (enoyl-CoA hydratase) → Oxidation (3-hydroxyacyl-CoA dehydrogenase, produces NADH) → Thiolysis (thiolase, releases acetyl CoA).

2. B - Long-chain fatty acyl CoA cannot cross the inner mitochondrial membrane on its own. The carnitine shuttle (CPT-I, translocase, CPT-II) transfers the acyl group across. Short-chain and medium-chain FAs enter without carnitine.

3. B - MCAD deficiency is the most common fatty acid oxidation disorder. It presents with hypoketotic hypoglycemia, dicarboxylic aciduria (C8-C10 species), and elevated medium-chain acylcarnitines. Often triggered by fasting.

4. C - Palmitoyl-CoA (C16) undergoes 7 rounds of beta-oxidation yielding 7 FADH2 + 7 NADH + 8 acetyl CoA. 8 acetyl CoA × 10 ATP = 80; 7 NADH × 2.5 = 17.5; 7 FADH2 × 1.5 = 10.5. Subtract 2 ATP for activation. Total ≈ 106 ATP (classic calculation gives 129 by older P/O ratios; the answer depends on the convention used - Devlin uses ~129 with older 3/2 P:O ratios).

5. A - Oleic acid (Δ9, cis) requires enoyl-CoA isomerase to convert the cis-Δ3 intermediate to trans-Δ2-enoyl-CoA (the normal beta-oxidation substrate). Polyunsaturated fatty acids require both isomerase and a reductase.

6. C - Omega-oxidation occurs in the smooth endoplasmic reticulum (microsomes), catalyzed by cytochrome P450 mixed-function oxidases (CYP4A family).

7. A - The first step of omega-oxidation involves microsomal CYP4A enzymes (mixed-function oxidases) that hydroxylate the terminal (omega) carbon using NADPH and O2.

8. B - The tetrad of peripheral neuropathy, cerebellar ataxia, retinitis pigmentosa, and elevated phytanic acid is classic for Refsum disease (heredopathia atactica polyneuritiformis).

9. A - Refsum disease is caused by deficiency of phytanoyl-CoA alpha-hydroxylase (PHYH/PAHX), the enzyme that initiates alpha-oxidation of phytanic acid in peroxisomes.

10. A - Alpha-oxidation converts phytanic acid (a 3-methyl-branched fatty acid that cannot directly undergo beta-oxidation) to pristanic acid + CO2, allowing subsequent beta-oxidation.

11. C - Systemic primary carnitine deficiency results from mutations in OCTN2, the organic cation/carnitine transporter expressed in heart, muscle, and kidney, leading to urinary carnitine wasting.

12. A - In peroxisomes, the first oxidation step is performed by acyl-CoA oxidase (an FAD-dependent oxidase that transfers electrons directly to O2, generating H2O2, not FADH2). No carnitine is needed for fatty acid entry into peroxisomes.

13. C - During prolonged fasting, free fatty acids (from adipose lipolysis) are the predominant fuel for skeletal muscle. Ketone bodies are a secondary fuel. The brain adapts to using ketones but muscle primarily uses FAs.

14. B - MCAD deficiency is the most common inherited disorder of fatty acid oxidation and is a frequent cause of sudden unexplained infant death. It presents with microvesicular steatosis.

15. D - The liver cannot utilize ketone bodies as fuel because it lacks succinyl-CoA:acetoacetate CoA transferase (thiophorase). This enzyme is absent in hepatocytes, so ketones are exclusively exported.

16. B - Acetyl CoA carboxylase (ACC) catalyzes the carboxylation of acetyl CoA to malonyl CoA. This is the committed, rate-limiting step of fatty acid synthesis.

17. D - Citrate allosterically activates ACC by promoting polymerization of ACC monomers into active filaments. Palmitoyl CoA and AMPK-induced phosphorylation inhibit ACC.

18. B - Even in the ER elongation system, malonyl CoA provides the 2-carbon elongation unit.

19. C - Fatty acid synthesis (de novo lipogenesis) is a cytosolic process in liver, adipose, and lactating mammary gland.

20. B - Phosphatidate phosphatase (lipin) converts phosphatidic acid to diacylglycerol (DAG) and is considered a key regulatory step. DGAT (the final step) is also regulated but lipin is the key regulatory node.

21. B - CTP:phosphocholine cytidylyltransferase (CCT) is the rate-limiting enzyme that forms CDP-choline from CTP and phosphocholine in the CDP-choline (Kennedy) pathway.

22. B - Carnitine is required for the carnitine shuttle to transport long-chain fatty acyl CoA into mitochondria for beta-oxidation. Bariatric surgery can cause micronutrient deficiencies, including carnitine.

23. B - Malonyl CoA inhibits CPT-I, preventing fatty acid transport into mitochondria and thereby preventing beta-oxidation when lipogenesis is active. This is a key metabolic switch.

24. C - The pentose phosphate pathway (hexose monophosphate shunt) is the primary source of NADPH for fatty acid synthesis and cholesterol synthesis. Each turn produces 2 NADPH.

25. B - Sphingomyelin is synthesized from ceramide + phosphatidylcholine (PC), transferring the phosphocholine head group from PC to ceramide, catalyzed by sphingomyelin synthase.

26. B - Dipalmitoylphosphatidylcholine (DPPC, or dipalmitoyl lecithin) is the major surfactant component that reduces surface tension in alveoli. Deficiency causes neonatal respiratory distress syndrome (NRDS).

27. C - Insulin activates protein phosphatase 2A → dephosphorylates and activates ACC; insulin also activates SREBP-1c via the PI3K/Akt/mTORC1 pathway to transcriptionally upregulate lipogenic enzymes including FAS.

28. B - Excess free fatty acids delivered to the liver promote VLDL-TAG synthesis and secretion, contributing to hypertriglyceridemia seen in type 2 diabetes/metabolic syndrome.

29. B - HMG-CoA reductase (HMGCR), converting HMG-CoA to mevalonate, is the rate-limiting step and the target of statins.

30. B - All 27 carbons of cholesterol originate from acetyl CoA. Acetyl CoA → HMG-CoA → mevalonate → IPP → squalene → cholesterol.

31. B - Statins block hepatic cholesterol synthesis → less intracellular cholesterol → SCAP escorts SREBP-2 to Golgi → SREBP-2 is cleaved → LDL receptor gene transcription increases → more LDL cleared from plasma.

32. A - CYP7A1 (cholesterol 7-alpha-hydroxylase) is the rate-limiting enzyme converting cholesterol to 7-alpha-hydroxycholesterol, the first step in bile acid synthesis.

33. C - LDL >300-400 mg/dL with premature CAD and family history is typical of heterozygous familial hypercholesterolemia (FH). Homozygous FH has LDL >700 mg/dL and presents in childhood.

34. D - HDL mediates reverse cholesterol transport (RCT): collects peripheral cholesterol via ABC-A1/G1 transporters → esterifies it (LCAT) → delivers to liver via SR-B1 receptors or transfers to VLDL/LDL via CETP.

35. B - When cholesterol is high, it causes binding of INSIG proteins to SCAP → SCAP-SREBP complex is retained in the ER → no proteolytic cleavage of SREBP-2 → no transcriptional activation of LDL receptor or HMG-CoA reductase genes.

36. B - Ketogenesis occurs exclusively in hepatic mitochondria. The liver has high levels of HMG-CoA synthase (mitochondrial form) and lacks the thiophorase needed to utilize ketones.

37. C - Mitochondrial HMG-CoA synthase is the key enzyme unique to ketogenesis. (Cytosolic HMG-CoA synthase is involved in cholesterol synthesis.) It condenses acetoacetyl CoA with acetyl CoA → HMG-CoA.

38. C - In DKA, absolute insulin deficiency → maximal lipolysis of adipose TAG → massive fatty acid delivery to liver → acetyl CoA overproduction exceeds TCA capacity → ketone body formation (acetoacetate, beta-hydroxybutyrate).

39. C - Under normal conditions, the NADH/NAD+ ratio favors reduction of acetoacetate to beta-hydroxybutyrate, giving a 3:1 ratio (beta-OHB:acetoacetate). In DKA, this ratio increases further.

40. B - Acetone is formed by spontaneous, non-enzymatic decarboxylation of acetoacetate. It is exhaled (fruity/acetone breath) and has limited metabolic use. It is not produced by an enzyme.

41. D - The three ketone bodies are acetoacetate, beta-hydroxybutyrate, and acetone. Acetyl CoA is NOT a ketone body; it is the substrate for ketone body synthesis.

42. B - Succinyl-CoA:acetoacetate CoA transferase (thiophorase) activates acetoacetate to acetoacetyl CoA for utilization. This enzyme is present in all tissues EXCEPT the liver, preventing futile cycling.

43. C - HMG-CoA reductase is NOT inhibited by mevalonate itself; it undergoes feedback regulation by downstream products (oxysterols → accelerated degradation; INSIG binding). It is phosphorylated (inactivated) by AMPK and PKA, and dephosphorylated (activated) by insulin-stimulated phosphatase.

44. B - Low dietary protein and low insulin (from malnutrition) promote adipose lipolysis → fatty acid delivery to liver → ketogenesis. Ketones provide fuel for brain and muscle during protein-calorie malnutrition.

45. B - In the fed state, the liver receives portal glucose and amino acids → glycolysis → acetyl CoA → lipogenesis + glycogen synthesis. Excess lipid is packaged into VLDL and exported.

46. C - In early fasting (8-12 hours), the brain still relies primarily on glucose derived from hepatic glycogenolysis and emerging gluconeogenesis. Ketone body production is just beginning to rise.

47. C - Glucagon is the primary counter-regulatory hormone to insulin in regulating hepatic glucose and lipid metabolism. It activates PKA, which phosphorylates and inactivates glycogen synthase, ACC, and pyruvate kinase.

48. C - After several days of starvation, ketone bodies (acetoacetate and beta-hydroxybutyrate) supply up to 60-70% of brain energy requirements, significantly reducing the protein-sparing glucose requirement.

49. A - The Randle cycle describes the competition between glucose and fatty acids for oxidation in muscle and heart: when fatty acid oxidation is high, acetyl CoA inhibits PDH and citrate inhibits PFK-1, reducing glucose oxidation; and vice versa.

50. B - PFK-1 phosphorylates fructose-6-P → F-1,6-BP; FBPase-1 does the reverse. When both are simultaneously active (as can occur in certain metabolic states), ATP is wasted (substrate cycling).

51. C - Glucagon/cAMP activates PKA, which phosphorylates and INACTIVATES pyruvate kinase (L-isoform) in the liver, preventing futile cycling between PEP and pyruvate during gluconeogenesis. Options A, B, and D are all correctly activated by glucagon.

52. B - Glucogenic amino acids feed into TCA cycle intermediates (OAA, alpha-KG, succinyl-CoA, fumarate) or as pyruvate (which can be carboxylated to OAA by pyruvate carboxylase). From OAA, PEPCK generates PEP for gluconeogenesis.

53. B - The glucose-alanine cycle: muscle transamination (glutamate + pyruvate → alpha-KG + alanine) → alanine enters blood → liver takes up alanine → transamination to pyruvate → gluconeogenesis → glucose released back to muscle.

54. B - Acetyl CoA is the allosteric activator of pyruvate carboxylase (PC). High acetyl CoA (from beta-oxidation during fasting) signals that energy is available and gluconeogenic precursors are needed.

55. B - Malonyl CoA (generated by ACC in the fed/high-carbohydrate state) allosterically inhibits CPT-I, blocking fatty acid entry into mitochondria and preventing beta-oxidation when lipogenesis is occurring.

56. B - Type 1 DM is autoimmune, with T-cell-mediated and antibody-mediated destruction of pancreatic beta cells, leading to absolute insulin deficiency. Associated with HLA-DR3/DR4.

57. B - DKA is defined by: hyperglycemia (usually >250 mg/dL), ketonemia/ketonuria (beta-hydroxybutyrate elevated), and high-anion-gap metabolic acidosis (pH <7.3, bicarbonate <18 mEq/L, anion gap >12).

58. C - HbA1c reflects the non-enzymatic glycation of hemoglobin over the lifespan of a red blood cell (~120 days), giving an average of approximately 8-12 weeks (3 months).

59. B - In type 2 DM, the earliest defect is peripheral insulin resistance, particularly in skeletal muscle and adipose tissue. The pancreas initially compensates with increased insulin secretion (hyperinsulinemia) before beta cell failure.

60. B - GLUT-2 is expressed in hepatocytes and pancreatic beta cells. Its high Km (~15-20 mM) means glucose transport is proportional to blood glucose, making it a glucose sensor. Muscle and adipose use GLUT-4 (insulin-dependent).

61. B - Without insulin, GLUT-4 remains in intracellular vesicles and does not translocate to the cell surface → muscle and adipose cannot take up glucose. Simultaneously, glucagon (unopposed by insulin) activates gluconeogenesis and glycogenolysis, worsening hyperglycemia.

62. B - AGEs cross-link proteins, increase oxidative stress, and activate receptors (RAGE) → endothelial dysfunction → microvascular disease. This is the biochemical basis of diabetic retinopathy, nephropathy, and neuropathy.

63. B - Aldose reductase (NADPH-dependent) converts glucose to sorbitol. In hyperglycemia, this pathway is activated → sorbitol accumulates (impermeable) → osmotic damage + NADPH depletion → oxidative stress in lens, nerves, and retina.

64. B - MODY 2 (glucokinase MODY) is caused by heterozygous loss-of-function mutations in glucokinase, raising the glucose threshold for insulin secretion. It causes mild fasting hyperglycemia, often not requiring treatment.

65. B - The most common cause of hypoglycemia in a known diabetic is excess exogenous insulin (or sulfonylurea). Clinical features (diaphoresis from sympathetic activation, confusion from neuroglycopenia) are classic.

66. B - Metformin's primary mechanism is activation of AMPK → inhibition of hepatic gluconeogenesis (decreases expression of PEPCK and G6Pase). It does not cause hypoglycemia alone.

67. B - In type 1 DM, absolute insulin deficiency → unopposed glucagon → maximal activation of HSL in adipose → massive FFA release → hepatic beta-oxidation → excess acetyl CoA → HMG-CoA → ketone bodies. Type 2 patients retain enough insulin to partially suppress lipolysis.

68. C - The urea cycle is present almost exclusively in hepatocytes. The liver is the organ of nitrogen detoxification, converting toxic ammonia to urea for renal excretion.

69. B - Steps 1 and 2 (carbamoyl phosphate synthesis by CPS-I, and citrulline formation by OTC) occur in the mitochondrial matrix. The remaining steps (citrulline + aspartate → argininosuccinate → arginine → urea) occur in the cytoplasm.

70. B - One nitrogen of urea comes from free NH4+ (via CPS-I to carbamoyl phosphate); the other comes from aspartate (donated via argininosuccinate). Glutamate is the immediate nitrogen donor to both ammonia (via GDH) and aspartate (via transamination).

71. C - N-acetylglutamate (NAG), synthesized by NAG synthase from glutamate + acetyl CoA, is the obligate allosteric activator of CPS-I. Arginine (a product of the cycle) stimulates NAG synthase, providing positive feedback.

72. D - OTC deficiency is the most common urea cycle disorder (X-linked). It presents with severe hyperammonemia in neonates. Citrulline is absent/very low because OTC (mitochondrial) converts carbamoyl phosphate + ornithine → citrulline - this step is blocked. CPS-I deficiency would have a similar picture but OTC deficiency is more common.

73. A - ALT (GPT): Alanine + alpha-ketoglutarate ↔ Pyruvate + Glutamate. This is the key reaction linking amino acid metabolism and carbohydrate metabolism. Elevated ALT in serum indicates hepatocellular damage.

74. B - PLP (pyridoxal phosphate) is the essential cofactor for ALL aminotransferases (transaminases). It forms a Schiff base with the amino acid substrate and acts as an amino group carrier.

75. B - GDH is allosterically activated by ADP and leucine (signaling low energy and excess amino acid catabolism), and inhibited by GTP and ATP (high energy charge). This controls the rate of NH3 release.

76. C - Positive nitrogen balance (N intake > N excretion) occurs when net protein synthesis exceeds catabolism: pregnancy, childhood growth, anabolic steroid use, recovery from illness. Burns, starvation, and Cushing syndrome cause NEGATIVE nitrogen balance.

77. C - Alanine (from muscle transamination - glucose-alanine cycle) and glutamine (from glutamine synthetase in muscle) are the two principal vehicles for nitrogen transport from peripheral tissues to the liver, protecting against free ammonia toxicity.

78. B - Ammonia condenses with alpha-ketoglutarate to form glutamate (via GDH), and with glutamate to form glutamine (via glutamine synthetase). This depletes TCA cycle intermediates (alpha-KG) → impairs oxidative phosphorylation in astrocytes → brain energy failure. Glutamine accumulation in astrocytes also causes osmotic swelling → cerebral edema.

79. C - Thyroid hormones (T3/T4) and all steroid hormones (glucocorticoids, mineralocorticoids, sex steroids) act via intracellular/nuclear receptors that function as ligand-activated transcription factors.

80. B - Glucagon and beta-adrenergic catecholamines bind GPCRs linked to Gs protein → activates adenylyl cyclase → converts ATP to cAMP → activates PKA → phosphorylates multiple metabolic enzymes.

81. B - The insulin receptor is a receptor tyrosine kinase (RTK). Insulin binding → autophosphorylation → phosphorylation of IRS-1 → recruitment of PI3K → PIP3 → Akt activation → GLUT-4 translocation, glycogen synthesis, protein synthesis, lipogenesis.

82. C - Nitric oxide (produced by NOS from arginine) diffuses into smooth muscle cells and binds to the heme of soluble guanylyl cyclase (sGC) → activates sGC → converts GTP to cGMP → activates PKG → smooth muscle relaxation and vasodilation.

83. C - Glucagon, epinephrine (beta), TSH, LH, FSH, PTH, ACTH, and ADV all signal via GPCRs. Many are linked to Gs (increases cAMP) while some (e.g., alpha-1 adrenergic) are linked to Gq (increases IP3/DAG).

84. C - Sildenafil inhibits PDE-5 → cGMP accumulates → persistent vasodilation of penile vasculature. This is the NO-cGMP pathway. This same pathway is used therapeutically in pulmonary arterial hypertension (PAH).

85. B - Steroid hormones (glucocorticoids, mineralocorticoids, estrogens, androgens, progesterone) are lipid-soluble → diffuse across membrane → bind intracellular receptors → receptor-hormone complex translocates to nucleus → binds hormone response elements (HREs) → alters gene transcription.

86. B - Growth hormone, prolactin, erythropoietin, leptin, and most cytokines (interferons, interleukins) signal through the JAK-STAT (Janus kinase - Signal Transducer and Activator of Transcription) pathway, as they lack intrinsic kinase activity.

87. C - Thyroid hormones (T3, T4) are iodinated derivatives of tyrosine. Two tyrosine residues (as part of thyroglobulin) are iodinated and coupled to form T4 or T3.

88. B - Thyroid peroxidase (TPO) catalyzes: (1) oxidation of iodide to iodine (organification/iodination of tyrosines on thyroglobulin to form MIT and DIT), and (2) coupling of MIT+DIT → T3, or DIT+DIT → T4. Carbimazole and PTU inhibit TPO.

89. B - T3 is 3-5x more potent than T4 at the nuclear receptor. T4 is the main secretory product of the thyroid but is converted to T3 (active form) in peripheral tissues by 5'-deiodinase. Reverse T3 is biologically inactive.

90. B - Graves disease: autoimmune hyperthyroidism caused by TSH-receptor stimulating antibodies (TRAb/TSAB). Classic features include low TSH (suppressed by negative feedback), high free T4/T3, diffuse goiter, and exophthalmos (thyroid eye disease).

91. B - PTU has a dual mechanism: it inhibits TPO (blocking iodination and coupling) AND inhibits type 1 deiodinase (blocking peripheral T4→T3 conversion). Methimazole only inhibits TPO. PTU is preferred in thyroid storm and first trimester pregnancy.

92. B - Thyroid hormones increase BMR by upregulating Na+/K+-ATPase (increasing O2 consumption); stimulate both cholesterol synthesis and degradation via LDL receptors (net effect: lower LDL/cholesterol - hence hypothyroidism causes hypercholesterolemia); increase protein synthesis and carbohydrate metabolism.

93. C - The adrenal cortex zones (outside to inside): Zona Glomerulosa → Mineralocorticoids (aldosterone); Zona Fasciculata → Glucocorticoids (cortisol); Zona Reticularis → Sex steroids (DHEA, androgens). Mnemonic: "GFR" - Salt, Sugar, Sex.

94. B - Cortisol promotes gluconeogenesis (induces PEPCK, G6Pase, tyrosine aminotransferase), protein catabolism in peripheral muscle (releases amino acids as gluconeogenic substrates), lipolysis (central fat redistribution), and has potent anti-inflammatory/immunosuppressive effects.

95. C - Cushing syndrome: chronic excess glucocorticoids. Features reflect cortisol's metabolic effects: central adiposity, moon face, buffalo hump (lipogenesis stimulated centrally), striae (skin protein loss), HTN, hyperglycemia, and immunosuppression. May be ACTH-dependent (Cushing disease = pituitary adenoma) or independent (adrenal adenoma, exogenous steroids).

96. B - Addison disease (primary adrenal insufficiency): destruction of adrenal cortex → low cortisol AND low aldosterone → HIGH ACTH and renin (loss of negative feedback). Clinically: hypotension, hyponatremia, hyperkalemia, hyperpigmentation (elevated ACTH/MSH), hypoglycemia.

97. B - 21-hydroxylase (CYP21A2) deficiency accounts for >90% of CAH. It blocks cortisol (and aldosterone in severe forms) synthesis → elevated ACTH → adrenal hyperplasia → precursors shunted to androgen synthesis → virilization. Salt-wasting occurs in complete deficiency.

98. A - Catecholamine synthesis: Phenylalanine → (phenylalanine hydroxylase) → Tyrosine → (tyrosine hydroxylase, rate-limiting) → DOPA → (DOPA decarboxylase, needs PLP) → Dopamine → (dopamine beta-hydroxylase, in vesicles) → Norepinephrine → (PNMT, in adrenal medulla only) → Epinephrine.

99. C - Pheochromocytoma is a catecholamine-secreting tumor of the adrenal medulla. Classic triad: episodic hypertension + headache + diaphoresis + palpitations. Diagnosis: elevated urine/plasma metanephrines or catecholamines. Associated with MEN 2A/2B, VHL, NF1.

100. B - Aldosterone (via its nuclear mineralocorticoid receptor) induces synthesis of ENaC (epithelial Na+ channels), Na+/K+-ATPase, and serum glucocorticoid kinase (SGK1) in principal cells of DCT and collecting duct → Na+ reabsorption, K+ excretion, water follows Na+ → expanded ECF volume and hypertension in excess.

Total: 100 Questions | 8 Topics Covered

Topics breakdown:

Q1-15: Beta Oxidation, Carnitine Shuttle, Alpha/Omega Oxidation, Refsum Disease (15 Qs)
Q16-28: Fatty Acid Synthesis, TAG Synthesis, Membrane Lipids, Regulation (13 Qs)
Q29-44: Cholesterol, Ketone Bodies, Ketogenesis, Regulation (16 Qs)
Q45-55: Integration of Metabolism, Feed-Starve Cycle (11 Qs)
Q56-67: Diabetes - Classification and Biochemical Aspects (12 Qs)
Q68-78: Urea Cycle, Nitrogen Balance, Transamination/Deamination (11 Qs)
Q79-86: Hormones - Classification and Mechanism of Action (8 Qs)
Q87-100: Thyroid and Adrenal Hormones (14 Qs)

Good luck with your MBBS finals!

I have my mbbs final exam and it’s going to be an mcq exam I want you to creat 100 questions from the topics make sure they are theoretical as well as clinically based questions take reference from Emery’s elements of medical genetics © 2012 by Churchill Livingstone, an imprint of Elsevier Cancer genetics; * Immunogenetics: Innate Immunity, Specific Acquired Immunity. Immunogenetics: Inherited Immunodeficiency Disorders, Blood Groups Disease model for multifactorial inheritance; Diabetes Type I, Type II; Disorders of amino acid metabolism; Disorders Branched chain amino acid metabolism; Urea cycle Disorders Gene Therapy, Eugenics; dysgenics of medical genetics; Gene therapy. Androgen Insensitivity and congenital adrenal hyperplasia;

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Here are your 100 MBBS Final MCQs drawn directly from Emery's Elements of Medical Genetics.

100 MCQs - Medical Genetics (MBBS Final)

Reference: Emery's Elements of Medical Genetics, Churchill Livingstone/Elsevier

SECTION 1: Cancer Genetics

(Questions 1-15)

Q1. The "two-hit hypothesis" of carcinogenesis was originally proposed to explain the inheritance pattern of which tumor?

A) Breast cancer B) Retinoblastoma C) Wilms tumor (nephroblastoma) D) Neuroblastoma

Q2. According to the two-hit hypothesis, in a child who inherits a germline mutation in a tumor suppressor gene, what is the "second hit"?

A) A new germline mutation in the other allele B) A somatic mutation, deletion, or loss of heterozygosity in the remaining wild-type allele C) A chromosomal translocation creating a fusion oncogene D) Epigenetic silencing of a proto-oncogene

Q3. Which of the following chromosomal translocations is characteristically associated with chronic myeloid leukemia (CML)?

A) t(14;18) - BCL2/IgH B) t(9;22) - BCR-ABL1 (Philadelphia chromosome) C) t(8;14) - MYC/IgH D) t(15;17) - PML-RARA

Q4. Oncogenes differ from proto-oncogenes in that:

A) Proto-oncogenes are found only in tumor cells B) Oncogenes arise from proto-oncogenes by gain-of-function mutations that promote uncontrolled cell growth C) Oncogenes cause cancer only when both alleles are mutated D) Oncogenes code for proteins that suppress cell growth

Q5. The RET proto-oncogene is associated with which hereditary cancer syndrome?

A) Lynch syndrome (HNPCC) B) Familial adenomatous polyposis (FAP) C) Multiple endocrine neoplasia type 2 (MEN 2A and 2B) D) Von Hippel-Lindau disease

Q6. A 45-year-old woman has colorectal cancer. Her family history reveals her mother and two maternal uncles also had colorectal cancer and one uncle had endometrial cancer. Colonoscopy shows very few polyps. The most likely hereditary cancer syndrome is:

A) Familial adenomatous polyposis (FAP) B) Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer - HNPCC) C) Peutz-Jeghers syndrome D) MUTYH-associated polyposis

Q7. Familial adenomatous polyposis (FAP) is caused by a germline mutation in which gene?

A) BRCA1 B) APC (adenomatous polyposis coli) C) MLH1 D) VHL

Q8. The TP53 gene is the most commonly mutated gene in human cancers. TP53 functions as a:

A) Proto-oncogene that promotes cell division when mutated B) Tumor suppressor gene that arrests the cell cycle and promotes apoptosis in response to DNA damage C) DNA mismatch repair gene D) Receptor tyrosine kinase

Q9. A woman with a BRCA2 germline mutation is at increased risk for which of the following cancers?

A) Ovarian cancer and cervical cancer B) Breast cancer, ovarian cancer, and prostate cancer (in male carriers) C) Colon cancer and endometrial cancer D) Thyroid cancer and renal cancer

Q10. Loss of heterozygosity (LOH) is a mechanism by which:

A) An oncogene is amplified B) The remaining wild-type copy of a tumor suppressor gene is inactivated in a cell that already carries one mutant allele C) A chromosome translocation creates a fusion protein D) DNA methylation silences a proto-oncogene

Q11. Von Hippel-Lindau (VHL) syndrome is characterized by all of the following EXCEPT:

A) Hemangioblastomas of the cerebellum and retina B) Clear cell renal cell carcinoma C) Pheochromocytoma D) Medulloblastoma

Q12. Which of the following correctly describes the genetics of colorectal cancer in FAP?

A) A single germline APC mutation is sufficient to cause colorectal cancer directly B) A germline APC mutation (first hit) plus a somatic APC mutation (second hit) leads to adenoma formation; further somatic mutations are required for malignant transformation C) FAP follows autosomal recessive inheritance D) FAP is caused by mismatch repair gene mutations

Q13. A boy presents with a white papillary mass in his right eye at age 18 months. His father had bilateral retinoblastoma in childhood. This child's retinoblastoma is most likely:

A) Sporadic, unilateral, somatic only B) Hereditary (germline RB1 mutation), at high risk of bilateral disease and other tumors C) Caused by a BRCA1 mutation D) Due to an acquired BCR-ABL1 translocation

Q14. Peutz-Jeghers syndrome is characterized by:

A) Hundreds to thousands of colonic adenomas and germline APC mutation B) Hamartomatous polyps, mucocutaneous pigmentation (lips/buccal mucosa), and increased risk of GI and non-GI cancers; caused by STK11/LKB1 mutation C) Mismatch repair gene mutations and microsatellite instability D) Clear cell renal carcinoma and cerebellar hemangioblastoma

Q15. Microsatellite instability (MSI) is the hallmark of which hereditary cancer syndrome?

A) FAP (APC mutations) B) Hereditary breast/ovarian cancer (BRCA1/2) C) Lynch syndrome (mismatch repair gene mutations: MLH1, MSH2, MSH6, PMS2) D) Li-Fraumeni syndrome (TP53)

SECTION 2: Immunogenetics - Innate Immunity and Specific Acquired Immunity

(Questions 16-30)

Q16. The first line of defense against infection in innate immunity is:

A) Production of specific antibodies by B cells B) Mechanical barriers such as skin, acidic pH of sweat, mucous membranes, and bactericidal agents in body fluids C) Activation of cytotoxic T lymphocytes D) Memory cell formation

Q17. Toll-like receptors (TLRs) are key components of innate immunity. They are expressed on which cells?

A) Red blood cells and platelets only B) Dendritic cells, macrophages, NK cells, T cells, B cells, epithelial and endothelial cells C) Only B lymphocytes D) Only cytotoxic T cells

Q18. TLR2 in innate immunity primarily recognizes:

A) Double-stranded viral RNA B) Peptidoglycans and lipoproteins associated with gram-positive bacteria C) CpG DNA motifs of bacteria D) Lipopolysaccharide (LPS) of gram-negative bacteria

Q19. Macrophages destroy phagocytosed microorganisms by which mechanism?

A) Complement-mediated lysis only B) Exposure to hydrogen peroxide, hydroxyl radicals, and nitric oxide following fusion with intracellular granules C) Antibody-dependent cellular cytotoxicity (ADCC) only D) Perforin secretion

Q20. Natural killer (NK) cells belong to which arm of immunity?

A) Specific acquired (adaptive) immunity only B) Innate immunity - they recognize and kill virus-infected and tumor cells without prior sensitization C) Both innate and acquired immunity equally D) Humoral immunity only

Q21. The complement system can be activated by which pathways?

A) Only the classical pathway (antibody-antigen complexes) B) Classical pathway (antibody-antigen), alternative pathway (direct microbial surface), and lectin pathway (mannose-binding lectin) C) Only the alternative pathway in innate immunity D) Only through TLR signaling

Q22. A basic immunoglobulin (Ig) molecule is composed of:

A) Two heavy chains only B) Two heavy chains and two light chains, connected by disulfide bonds (4 polypeptide chains total) C) Six polypeptide chains D) One heavy chain and one light chain

Q23. The diversity of the antibody repertoire is generated primarily by:

A) Point mutations in the heavy chain constant region B) Somatic recombination (VDJ recombination) of gene segments in B cells, plus somatic hypermutation C) Alternative splicing of a single Ig gene D) Class switching only

Q24. MHC (HLA) class I molecules present antigen to:

A) CD4+ helper T cells B) CD8+ cytotoxic T cells C) B cells directly D) NK cells via activating receptors

Q25. MHC class II molecules (HLA-DR, DP, DQ) are expressed on:

A) All nucleated cells B) Professional antigen-presenting cells (dendritic cells, macrophages, B cells) C) Red blood cells and platelets D) Cytotoxic T lymphocytes exclusively

Q26. The role of CD4+ helper T cells in specific acquired immunity includes:

A) Direct cytotoxic killing of infected cells B) Secreting cytokines that activate B cells for antibody production and help cytotoxic T cell responses C) Presenting antigen to B cells via MHC class I D) Secreting perforin to lyse virus-infected cells

Q27. Immunological memory, the basis for vaccination, is mediated by:

A) Innate immune cells (macrophages and NK cells) B) Long-lived memory B cells and memory T cells generated after first antigen exposure C) Complement protein C3 stored in the liver D) Continuous antibody production by plasma cells in bone marrow only

Q28. Maternal antibodies (IgG) transferred to the infant transplacentally provide protection for approximately how long after birth?

A) 1-3 months B) Approximately 6 months (up to about 12 months in some classifications - Emery's states approximately 12 months protection) C) 2 years D) Lifelong protection

Q29. The T-cell receptor (TCR) diversity is generated by a mechanism analogous to:

A) Class switching in B cells B) VDJ recombination, similar to immunoglobulin gene rearrangement in B cells C) Somatic hypermutation only D) Alternative RNA splicing

Q30. Which immunoglobulin class is the most abundant in serum and is capable of crossing the placenta?

A) IgA B) IgM C) IgG D) IgE

SECTION 3: Inherited Immunodeficiency Disorders and Blood Groups

(Questions 31-43)

Q31. Severe Combined Immunodeficiency (SCID) is characterized by:

A) Isolated B cell deficiency only B) Profound deficiency of both T cells and B cells (combined cellular and humoral immunity) C) Normal T cells with absent NK cells D) Complement deficiency with normal lymphocytes

Q32. The most common form of X-linked SCID is caused by mutations in which gene?

A) ADA (adenosine deaminase) B) IL2RG (common gamma chain of the IL-2 receptor) C) RAG1 or RAG2 D) Bruton's tyrosine kinase (BTK)

Q33. Adenosine deaminase (ADA) deficiency causes SCID by:

A) Blocking VDJ recombination in T cells B) Accumulation of toxic deoxyadenosine metabolites that are specifically toxic to lymphocytes C) Defective IL-7 receptor signaling D) Absent MHC class II expression

Q34. DiGeorge syndrome (22q11.2 deletion) results in immunodeficiency primarily because of:

A) Absent B cells due to BTK mutation B) Aplasia or hypoplasia of the thymus → absent or reduced T cell development C) Complement deficiency D) Neutrophil dysfunction

Q35. Chronic Granulomatous Disease (CGD) is a disorder of which immune component?

A) T lymphocytes B) B lymphocytes and antibody production (humoral immunity) C) Phagocyte (neutrophil/macrophage) NADPH oxidase → inability to generate reactive oxygen species to kill catalase-positive organisms D) Complement system

Q36. X-linked agammaglobulinemia (Bruton disease) is caused by a mutation in BTK (Bruton's tyrosine kinase). This results in:

A) Absent T cells with normal B cells B) A block in B cell development → absent mature B cells → no antibody production; T cells are normal C) Combined T and B cell deficiency D) NK cell deficiency

Q37. A 6-month-old boy presents with recurrent sinopulmonary infections by encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) but no unusual viral or fungal infections. Serum immunoglobulins are markedly low. The most likely diagnosis is:

A) X-linked SCID B) DiGeorge syndrome C) X-linked agammaglobulinemia (Bruton disease) D) Chronic granulomatous disease

Q38. Hereditary angioedema (HAE) is caused by deficiency of:

A) C3 B) C1-esterase inhibitor (C1-INH) C) C5 D) Factor D (properdin pathway)

Q39. The ABO blood group system is determined by:

A) Antigens on the surface of lymphocytes B) Oligosaccharide antigens on the surface of red blood cells encoded by the ABO gene (glycosyltransferases on chromosome 9q34) C) Protein antigens encoded by genes on the X chromosome D) Serum antibody levels

Q40. A person with blood group O has:

A) Both A and B antigens on RBCs; anti-A and anti-B antibodies in serum B) Neither A nor B antigens on RBCs; both anti-A and anti-B antibodies in serum C) Only A antigen on RBCs; anti-B antibodies in serum D) Only B antigen on RBCs; anti-A antibodies in serum

Q41. Hemolytic disease of the newborn (HDN) most commonly involves which blood group antigen system?

A) ABO system B) Rhesus (Rh) system - anti-D antibodies C) Kell system D) Duffy system

Q42. In Rh incompatibility, the mother is Rh-negative. Why does severe HDN typically NOT occur in the FIRST pregnancy with an Rh-positive fetus?

A) The fetal Rh antigen is not expressed until after birth B) The first exposure generates a primary IgM response that does not cross the placenta; IgG memory antibodies develop only after sensitization, causing disease in subsequent pregnancies C) The placenta completely blocks all maternal antibodies in the first pregnancy D) Rh-negative mothers have natural tolerance to all fetal antigens

Q43. Wiskott-Aldrich syndrome (WAS) is an X-linked condition characterized by the triad of:

A) Thrombocytopenia, eczema, and recurrent infections (combined T and B cell dysfunction) B) Albinism, bleeding tendency, and neutropenia C) Absent thymus, hypocalcemia, and cardiac defects D) Recurrent bacterial infections only, with normal platelets

SECTION 4: Disease Model for Multifactorial Inheritance; Diabetes Type 1 and Type 2

(Questions 44-56)

Q44. The liability/threshold model for multifactorial inheritance proposes that:

A) A single major gene determines disease risk B) Disease liability is normally distributed in the population; individuals exceeding a threshold of liability (genetic + environmental factors) are affected C) Only environmental factors determine disease risk D) The disease follows autosomal dominant inheritance with reduced penetrance

Q45. Which of the following is a feature of multifactorial inheritance that distinguishes it from single-gene (Mendelian) inheritance?

A) Recurrence risk is the same regardless of the number of affected relatives B) Recurrence risk increases with the number of affected first-degree relatives and with increasing severity of the condition C) Risk is exactly 25% for siblings if both parents are carriers D) Male-to-male transmission is impossible

Q46. Which of the following conditions shows multifactorial inheritance?

A) Sickle cell disease B) Huntington disease C) Neural tube defects (spina bifida/anencephaly) D) Duchenne muscular dystrophy

Q47. The sibling recurrence risk for a multifactorial condition approximates the square root of the population incidence. If the incidence in the population is 1/400, what is the approximate sibling recurrence risk?

A) 1/400 B) 1/20 (5%) C) 1/4 (25%) D) 1/100

Q48. Periconceptional supplementation with folic acid reduces the risk of neural tube defects by approximately:

A) 10-20% B) 70-75% C) 30-40% D) 95%

Q49. In Type 1 Diabetes Mellitus (T1DM), the concordance rate in monozygotic (MZ) twins is approximately:

A) 100% (fully genetic) B) 25-30% C) Approximately 50% D) 10%

Q50. The strongest genetic association with T1DM is with which chromosomal region?

A) Chromosome 11p15 (INS gene) B) Chromosome 6p21 (HLA region) C) Chromosome 7q (TCF7L2) D) Chromosome 2q (CTLA4)

Q51. The pathological process underlying T1DM involves:

A) Peripheral insulin resistance with beta cell exhaustion B) Autoimmune destruction of insulin-producing beta cells in the islets of Langerhans by the immune system C) Mitochondrial dysfunction in pancreatic cells D) Glucokinase mutation reducing insulin secretion threshold

Q52. HLA DR3 and/or DR4 are found in approximately what percentage of T1DM patients (compared to ~50% of the general population)?

A) 60% B) 75% C) 95% D) 100%

Q53. The INS VNTR (variable number tandem repeat) locus on chromosome 11p15 influences T1DM susceptibility because:

A) Short VNTR repeats (class I) convey susceptibility; long repeats (class III) convey protection by increasing insulin expression in the fetal thymus → central tolerance to insulin B) Long repeats cause overexpression of insulin in the pancreas C) VNTR polymorphisms directly destroy beta cells D) Short VNTR repeats increase MHC class II expression

Q54. Compared to T1DM, the concordance in MZ twins for Type 2 Diabetes Mellitus (T2DM) is:

A) Lower (~30%) than T1DM, suggesting less genetic contribution B) Higher (>60-90%), suggesting a stronger genetic component with environmental triggers C) Identical (~50%) to T1DM D) Nearly 100%, showing complete genetic determination

Q55. MODY (Maturity-Onset Diabetes of the Young) is distinguished from T2DM by:

A) It is strongly associated with HLA-DR3/DR4 B) It follows monogenic (single-gene) autosomal dominant inheritance, with young onset and no insulin dependence initially C) It is caused by autoimmune beta cell destruction D) It requires insulin from the time of diagnosis

Q56. Gestational diabetes is important because:

A) It resolves permanently after delivery and carries no future risk B) Affected women have an increased risk of developing T2DM later in life, and fetal macrosomia is a risk C) It is caused by autoimmune beta cell destruction identical to T1DM D) It only occurs in women with pre-existing monogenic diabetes

SECTION 5: Disorders of Amino Acid Metabolism, Branched-Chain Amino Acid Metabolism, Urea Cycle Disorders

(Questions 57-70)

Q57. Phenylketonuria (PKU) results from deficiency of which enzyme?

A) Tyrosine aminotransferase B) Phenylalanine hydroxylase (PAH) C) Homogentisate oxidase D) Maleylacetoacetate isomerase

Q58. An untreated child with PKU will develop:

A) Premature cardiovascular disease and thrombophilia B) Severe intellectual disability, seizures, fair skin and hair (due to reduced melanin), and "mousy" urine odor C) Progressive liver failure and cirrhosis D) Cataracts and lens dislocation

Q59. The treatment of PKU involves:

A) Enzyme replacement therapy with recombinant PAH B) A phenylalanine-restricted diet (low but not zero phenylalanine, as it is an essential amino acid) with regular blood phenylalanine monitoring C) Complete elimination of all amino acids from the diet D) Liver transplantation

Q60. Alkaptonuria is caused by deficiency of homogentisate oxidase. The characteristic clinical feature that clinches the diagnosis in a clinical scenario is:

A) Elevated blood phenylalanine B) Darkening of urine on standing (homogentisic aciduria) and ochronosis (dark pigmentation of connective tissue) C) Maple-syrup-scented urine D) Lens dislocation and Marfanoid habitus

Q61. Maple Syrup Urine Disease (MSUD) is caused by deficiency of:

A) Cystathionine beta-synthase B) Branched-chain ketoacid decarboxylase (branched-chain alpha-keto acid dehydrogenase complex) C) Phenylalanine hydroxylase D) Galactose-1-phosphate uridyl transferase

Q62. The branched-chain amino acids that accumulate in MSUD are:

A) Phenylalanine, tyrosine, tryptophan B) Leucine, isoleucine, and valine C) Methionine, cysteine, and homocysteine D) Glutamine, asparagine, and glutamate

Q63. An untreated newborn with MSUD typically presents with:

A) Liver failure and jaundice in the first week B) Vomiting, alternating hypo/hypertonia, and maple-syrup-scented urine in the first week of life, progressing to death if untreated C) Gradual intellectual disability without acute illness D) Cataracts and galactosuria

Q64. Homocystinuria caused by cystathionine beta-synthase deficiency resembles Marfan syndrome in some features. Which feature is UNIQUE to homocystinuria and NOT seen in Marfan syndrome?

A) Tall stature and arachnodactyly B) Lens dislocation C) Intellectual disability and thrombophilia (venous and arterial thromboses) D) Pectus excavatum and scoliosis

Q65. The cyanide-nitroprusside test is used to screen for which condition?

A) PKU B) MSUD C) Homocystinuria (detects excess urinary homocysteine) D) Alkaptonuria

Q66. The urea cycle converts ammonia and bicarbonate to urea. The number of enzymatic steps in the urea cycle is:

A) Three B) Five C) Seven D) Two

Q67. Ornithine transcarbamylase (OTC) deficiency differs from all other urea cycle disorders in that it is:

A) Autosomal recessive with equal sex incidence B) X-linked (OTC gene on Xp21.1), affecting males more severely; females may be carriers with variable expression C) Autosomal dominant with high penetrance D) Caused by a mitochondrial DNA mutation

Q68. The biochemical hallmark of urea cycle disorders is:

A) Elevated serum phenylalanine B) Elevated plasma ammonia (hyperammonemia) C) Elevated blood lactate D) Elevated urine glucose

Q69. A 2-day-old neonate presents with poor feeding, lethargy, vomiting, and seizures after the introduction of protein feeding. Blood ammonia is markedly elevated. Plasma citrulline is undetectable. The most likely enzyme deficiency is:

A) Arginase deficiency B) Argininosuccinate lyase deficiency C) OTC deficiency or CPS-I deficiency (citrulline undetectable in both) D) Citrin deficiency

Q70. Which of the following correctly describes citrullinemia type I (argininosuccinate synthetase deficiency)?

A) X-linked disorder with absent citrulline in plasma B) Autosomal recessive; markedly elevated plasma citrulline (citrulline cannot be converted to argininosuccinate) C) Autosomal dominant; treated with dietary protein only D) Caused by a mitochondrial mutation

SECTION 6: Gene Therapy

(Questions 71-80)

Q71. Gene therapy can be classified into two broad types based on the target cells. These are:

A) Dominant and recessive gene therapy B) Somatic gene therapy (targeting non-reproductive cells) and germline gene therapy (targeting germ cells/embryos) C) Ex vivo and in vivo therapy only (these are delivery methods, not types) D) Viral and non-viral gene therapy

Q72. Which of the following is a viral vector commonly used in gene therapy?

A) Liposomes B) Adeno-associated viruses (AAV) C) Antisense oligonucleotides D) Plasmid DNA alone

Q73. Gene therapy using retroviral vectors carries the risk of insertional mutagenesis. This means:

A) The retroviral vector cannot integrate into the host genome B) Random insertion of the therapeutic gene into the host genome may activate an oncogene, potentially leading to malignancy C) The retrovirus causes direct cytotoxicity to target cells D) Retroviral vectors only work in dividing cells, limiting their use

Q74. Gene therapy was first successfully used to treat which condition?

A) Cystic fibrosis B) Duchenne muscular dystrophy C) Adenosine deaminase (ADA) deficiency - a form of SCID D) Sickle cell disease

Q75. Ex vivo gene therapy involves:

A) Direct injection of viral vector into the patient's bloodstream B) Removing cells from the patient, genetically modifying them in the laboratory, and returning them to the patient C) Oral administration of recombinant DNA D) Using CRISPR exclusively

Q76. Antisense oligonucleotides used in gene therapy work by:

A) Introducing a functional gene into the nucleus B) Binding to complementary mRNA sequences → blocking translation or triggering mRNA degradation C) Increasing transcription of the defective gene D) Replacing the defective protein directly

Q77. Which of the following is a potential gene therapy approach for cancer?

A) Introducing tumor suppressor genes into tumor cells B) Stimulating the immune system to attack tumor cells C) Using RNA interference (RNAi) to silence oncogenes D) All of the above

Q78. Adeno-associated virus (AAV) vectors are preferred in many gene therapy applications because:

A) They integrate permanently into the genome, ensuring long-term expression B) They can infect both dividing and non-dividing cells, have low immunogenicity, and are generally considered safe C) They have a very large cargo capacity (>30 kb) D) They replicate autonomously within the host cell

Q79. The ethical concern unique to germline gene therapy (compared to somatic gene therapy) is:

A) It is less effective than somatic gene therapy B) Genetic changes would be heritable and passed to future generations without their consent C) It cannot be used to treat single-gene disorders D) Germline gene therapy has already been approved in most countries

Q80. CRISPR-Cas9 technology in gene therapy acts by:

A) Delivering mRNA encoding a therapeutic protein B) Using a guide RNA to direct the Cas9 nuclease to cut specific DNA sequences, enabling precise gene editing (correction, insertion, or deletion) C) Blocking epigenetic methylation of promoter regions D) Producing antisense RNA to degrade defective mRNA

SECTION 7: Eugenics and Dysgenics of Medical Genetics

(Questions 81-86)

Q81. Eugenics is defined as:

A) The scientific study of genetic diseases in families B) The attempt to improve the genetic qualities of a human population by selective breeding - encouraging reproduction of "desirable" traits (positive eugenics) and discouraging reproduction of "undesirable" traits (negative eugenics) C) The study of how genes interact with the environment D) The ethical management of gene therapy

Q82. Which of the following represents "negative eugenics"?

A) Encouraging intellectually gifted individuals to have more children B) Compulsory sterilization of individuals with certain disabilities or diseases, as practiced in early 20th-century programs C) Genetic counseling that provides non-directive reproductive advice D) Newborn screening programs to identify treatable metabolic conditions

Q83. "Dysgenics" refers to concerns that:

A) Gene therapy will replace natural selection B) Medical advances that allow individuals with genetic diseases to survive and reproduce may gradually increase the frequency of deleterious alleles in the population C) Genetic testing will reduce genetic diversity D) Recombinant DNA technology creates new pathogens

Q84. Modern medical genetics distinguishes itself from historical eugenics programs primarily by:

A) Using the same selective breeding principles but with genetic technology B) Emphasizing non-directive genetic counseling, individual autonomy, and informed consent - NOT imposing reproductive decisions on individuals C) Focusing only on preventing severe autosomal recessive conditions D) Requiring government approval for all reproductive decisions

Q85. Genetic counseling, as practiced ethically in modern medicine, should be:

A) Directive - telling couples whether they should have children B) Non-directive - providing information about risks and options while respecting the couple's autonomy to make their own reproductive decisions C) Restricted to couples who already have an affected child D) Focused solely on termination of pregnancy as the only option for high-risk couples

Q86. The principal ethical argument AGAINST germline gene editing in humans (as opposed to somatic gene therapy) draws on concerns similar to historical eugenics concerns. This argument is:

A) Germline editing is technically impossible B) Future generations who would carry the edited genome have not consented, and population-level effects on human genetic diversity are unpredictable C) It costs too much to implement D) It would only work for recessive conditions

SECTION 8: Androgen Insensitivity Syndrome and Congenital Adrenal Hyperplasia

(Questions 87-100)

Q87. Complete Androgen Insensitivity Syndrome (CAIS) has the karyotype and phenotype:

A) 46,XX with virilized external genitalia B) 46,XY with complete female external phenotype (female external genitalia, absent uterus, absent or rudimentary Mullerian structures, testes in the inguinal canal or labial folds) C) 45,X with Turner phenotype D) 47,XXY with Klinefelter phenotype

Q88. Complete androgen insensitivity syndrome (CAIS) is caused by:

A) Deficiency of 5-alpha reductase enzyme B) Loss-of-function mutations in the androgen receptor (AR) gene on the X chromosome → androgen receptor cannot bind testosterone/DHT C) Deficiency of 21-hydroxylase in the adrenal gland D) Absent SRY gene on the Y chromosome

Q89. In CAIS, testosterone levels are typically:

A) Low (in the female reference range) B) Normal or elevated male range (high) - but cannot act due to absent functional receptor C) Undetectable D) Variable, similar to 46,XX females

Q90. Partial Androgen Insensitivity Syndrome (PAIS) differs from CAIS in that:

A) PAIS is caused by 5-alpha reductase deficiency B) PAIS results from partial AR function - external genitalia are ambiguous (between male and female phenotype) C) PAIS only affects testicular development, not external genitalia D) PAIS has a 46,XX karyotype

Q91. 5-alpha reductase type 2 deficiency results in:

A) Complete female phenotype in a 46,XY individual (CAIS) B) 46,XY individuals with ambiguous or female-appearing genitalia at birth, but virilization (clitoromegaly/phallic enlargement) at puberty due to rising testosterone C) Virilization of a 46,XX female fetus D) Primary amenorrhea in a 46,XX female

Q92. Congenital Adrenal Hyperplasia (CAH) most commonly results from deficiency of which enzyme?

A) 11-beta-hydroxylase (CYP11B1) B) 17-alpha-hydroxylase (CYP17) C) 21-hydroxylase (CYP21A2) D) 3-beta-hydroxysteroid dehydrogenase

Q93. The enzymatic block in 21-hydroxylase deficiency results in impaired synthesis of which two hormones?

A) Testosterone and estrogen B) Cortisol and aldosterone (with shunting of precursors to androgen synthesis) C) Growth hormone and IGF-1 D) Adrenaline and noradrenaline

Q94. The most common clinical form of 21-hydroxylase deficiency CAH with salt-wasting presents in a neonate with:

A) Hypertension and hypokalemia B) Virilization of external genitalia in females (46,XX); in males, both sexes show adrenal crisis with hyponatremia, hyperkalemia, and hypotension (salt-wasting crisis) C) Mild hyperglycemia and no genital abnormality D) Tall stature and premature puberty only

Q95. The inheritance pattern of CAH (21-hydroxylase deficiency) is:

A) X-linked recessive B) Autosomal dominant with variable expressivity C) Autosomal recessive (CYP21A2 gene on chromosome 6p21, near HLA) D) Mitochondrial

Q96. A pregnant woman is known to be at risk of carrying a fetus with classic 21-hydroxylase deficiency CAH. To prevent virilization of an affected female fetus, treatment with which agent is used?

A) Testosterone B) Dexamethasone (a glucocorticoid that crosses the placenta and suppresses fetal ACTH → reduces androgen production) C) Progesterone D) Spironolactone

Q97. Long-term treatment of classic CAH involves:

A) Hydrocortisone (glucocorticoid replacement) to suppress ACTH and reduce androgen excess; fludrocortisone (mineralocorticoid) in salt-wasting forms B) High-dose testosterone supplementation C) Surgical removal of the adrenal glands D) Dietary salt restriction only

Q98. 11-beta-hydroxylase deficiency CAH presents differently from 21-hydroxylase deficiency in that it causes:

A) Salt wasting and hypotension B) Hypertension and hypokalemia (due to accumulation of 11-deoxycorticosterone, a potent mineralocorticoid), along with virilization C) No genital abnormalities in either sex D) Pure glucocorticoid deficiency without androgen excess

Q99. A 46,XX infant presents with ambiguous genitalia at birth. ACTH stimulation test shows markedly elevated 17-hydroxyprogesterone. Electrolytes show hyponatremia and hyperkalemia. The diagnosis is:

A) Complete androgen insensitivity syndrome B) Classic salt-wasting 21-hydroxylase deficiency CAH C) 5-alpha reductase deficiency D) 11-beta-hydroxylase deficiency CAH

Q100. In complete androgen insensitivity syndrome (CAIS), when should the undescended testes be removed, and why?

A) Immediately at birth, because they produce harmful testosterone B) After puberty is complete (approximately age 16-20), because the testes produce estrogen (via aromatization of testosterone) allowing natural feminizing puberty; they are removed post-puberty due to ~2-3% lifetime risk of gonadal malignancy (gonadoblastoma/dysgerminoma) C) At age 5 to prevent hernia complications D) They should never be removed, as they have no malignant potential

ANSWER KEY WITH EXPLANATIONS

1. B - The two-hit hypothesis was proposed by Knudson in 1971 to explain retinoblastoma. Hereditary cases inherit one mutant RB1 allele (first hit) and only need one somatic mutation to lose the second copy. This explains why hereditary cases are bilateral/multifocal at a younger age.

2. B - In the hereditary form, the first hit is a germline mutation in one allele. The second hit is a somatic event (point mutation, deletion, LOH) that inactivates the remaining wild-type allele in a retinal cell → complete loss of tumor suppressor function → uncontrolled cell division.

3. B - The Philadelphia chromosome (Ph1) results from t(9;22), fusing BCR to ABL1, creating a constitutively active tyrosine kinase. This is the diagnostic translocation in CML and also present in ~25% of adult ALL. It is the target of imatinib (Gleevec).

4. B - Proto-oncogenes are normal cellular genes involved in growth and differentiation. Gain-of-function mutations (point mutations, amplification, translocation) convert them to oncogenes, which promote proliferation even without normal growth signals. Importantly, only ONE mutant allele is needed (dominant).

5. C - The RET proto-oncogene (receptor tyrosine kinase) is activated by germline gain-of-function mutations in MEN 2A (medullary thyroid cancer + pheochromocytoma + parathyroid adenoma) and MEN 2B (medullary thyroid cancer + pheochromocytoma + mucosal neuromas). RET mutations are an exception to the general rule that hereditary cancer genes are tumor suppressors.

6. B - Lynch syndrome (HNPCC) is caused by germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2). It presents as colorectal cancer with few polyps, often right-sided, at a younger age, with associated endometrial, ovarian, gastric, and urothelial cancers. Amsterdam criteria require 3 relatives in 2 generations with CRC.

7. B - FAP is caused by germline APC (adenomatous polyposis coli) mutations on chromosome 5q21. APC is a tumor suppressor that regulates the Wnt/beta-catenin signaling pathway. FAP is autosomal dominant; affected individuals develop hundreds to thousands of colorectal adenomas and have near 100% risk of colorectal cancer if untreated.

8. B - TP53 (chromosome 17p13) encodes the p53 protein - "guardian of the genome." On DNA damage, p53 activates cell cycle arrest (via p21/CDKN1A) and apoptosis. It is mutated in >50% of all human cancers. Germline TP53 mutations cause Li-Fraumeni syndrome.

9. B - BRCA2 (chromosome 13q12) mutations confer increased risk of breast cancer (~45-70% lifetime risk), ovarian cancer (~10-30%), and prostate cancer in male carriers (~20%), as well as pancreatic cancer. BRCA1 carries higher ovarian cancer risk.

10. B - LOH describes the somatic loss of the remaining wild-type allele of a tumor suppressor gene in a cell that already has one mutant allele. Mechanisms include deletion, mitotic recombination, gene conversion, or entire chromosome loss. This is the "second hit" of Knudson's hypothesis.

11. D - VHL syndrome features: hemangioblastomas (cerebellum, spinal cord, retina), clear cell renal cell carcinoma, pheochromocytoma, pancreatic cysts. Medulloblastoma is NOT a feature of VHL; it is seen in Gorlin syndrome (Nevoid Basal Cell Carcinoma syndrome, PTCH1 mutations).

12. B - One germline APC mutation is NOT sufficient. The APC tumor suppressor requires biallelic inactivation (two-hit model). The germline mutation provides the first hit; somatic mutation provides the second. Then multiple further somatic mutations (K-RAS, SMAD4, TP53, chromosomal instability) drive progression from adenoma to carcinoma (the adenoma-carcinoma sequence).

13. B - A positive family history (father with bilateral retinoblastoma) indicates a hereditary (autosomal dominant) RB1 germline mutation. This child is at high risk for bilateral disease, multifocal tumors, early onset, and secondary malignancies (osteosarcoma, other sarcomas) due to the germline mutation predisposing all cells.

14. B - Peutz-Jeghers syndrome: STK11/LKB1 gene (chromosome 19p) mutations cause hamartomatous polyps (throughout GI tract), mucocutaneous melanin spots (lips, buccal mucosa, fingertips), and increased risk of GI cancers, breast, ovarian, cervical, and pancreatic cancers.

15. C - Lynch syndrome (HNPCC) is caused by germline mutations in MMR genes. MMR gene deficiency → microsatellite instability (MSI-H) due to failure to correct replication errors at short repetitive sequences. MSI is both a diagnostic marker for Lynch syndrome and a prognostic/predictive biomarker.

16. B - The first line of defense (innate physical/chemical barriers): intact skin (impermeable), acidic pH of sweat (inhibits bacteria), mucous membranes, cilia in the respiratory tract, and bactericidal agents (lysozyme in tears, gastric acid). These prevent pathogen entry before immune cells are needed.

17. B - TLRs are expressed on professional immune cells (dendritic cells, macrophages, NK cells, T and B cells) and non-immune cells (epithelial cells, endothelial cells, fibroblasts), making innate immune surveillance ubiquitous. There are 10 TLRs in humans.

18. B - TLR2 is well characterized for recognizing peptidoglycans and lipoproteins from gram-positive bacteria. TLR4 recognizes LPS (gram-negative bacteria). TLR3 recognizes double-stranded RNA (viral). TLR9 recognizes CpG DNA.

19. B - After phagocytosis, the phagosome fuses with lysosomes → the organism is exposed to a respiratory burst generating reactive oxygen species (H2O2, hydroxyl radicals, superoxide) and reactive nitrogen species (nitric oxide). This oxidative killing is the primary bactericidal mechanism. CGD results from failure of this process.

20. B - NK cells are lymphoid cells of the innate immune system. They do not require prior sensitization or MHC-mediated antigen presentation. They kill target cells that have downregulated MHC class I (a common viral/tumor evasion mechanism) using the "missing self" strategy.

21. B - All three complement activation pathways converge at C3 cleavage: Classical (Ig-antigen complexes → C1q), Alternative (direct pathogen surface → spontaneous C3 hydrolysis + factor B/D/properdin), and Lectin (MBL binding mannose on pathogens → MASP1/2).

22. B - The basic Ig molecule (monomer) consists of 2 identical heavy (H) chains and 2 identical light (L) chains held together by disulfide bonds - 4 polypeptide chains total. IgM is a pentamer (10 chains × 5 monomers = with J chain). Answer C (6 chains) is incorrect.

23. B - The V(D)J recombination of variable (V), diversity (D), and joining (J) gene segments in B cells (for Ig) and T cells (for TCR) generates enormous combinatorial diversity. Somatic hypermutation in germinal centers further increases antibody specificity/affinity. Class switching changes the isotype without changing antigen specificity.

24. B - MHC class I (HLA-A, B, C) presents endogenous peptides (from intracellular proteins, viruses) to CD8+ cytotoxic T lymphocytes (CTLs). The rule: "Class I to CD8, Class II to CD4." CD8 acts as co-receptor binding to MHC class I; CD4 binds to MHC class II.

25. B - MHC class II molecules are expressed constitutively on professional APCs: dendritic cells, macrophages, B cells. They present exogenous antigens (taken up by phagocytosis/endocytosis) to CD4+ helper T cells. Class II expression can be induced on other cells by IFN-gamma.

26. B - Th1 CD4+ cells secrete IFN-gamma, TNF-alpha (activate macrophages, promote CTL responses); Th2 CD4+ cells secrete IL-4, IL-5, IL-13 (promote B cell class switching to IgE, eosinophil activation). CD4+ cells are essential "orchestrators" of both humoral and cellular adaptive immunity.

27. B - Primary immune response generates effector cells and memory cells. Memory B cells (long-lived, expressing high-affinity Ig due to somatic hypermutation) and memory T cells persist. On re-exposure, memory cells respond faster, more strongly, and with higher affinity antibodies (secondary response) - the basis of vaccines.

28. B - Maternal IgG crosses the placenta actively via the FcRn receptor. It provides passive protection to the neonate for approximately 6 months as maternal antibody is catabolized. Emery's describes protection for approximately 12 months. Active immune protection starts when the infant's own immune system matures.

29. B - The T-cell receptor (alpha/beta or gamma/delta chains) genes undergo V(D)J recombination analogous to immunoglobulin gene rearrangement. The RAG1/RAG2 enzymes mediate both processes. TCR diversity, like antibody diversity, is vast (~10^18 combinations).

30. C - IgG is the most abundant serum immunoglobulin (~75% of total). It is the only isotype that crosses the placenta (via FcRn receptor) to provide passive immunity to the neonate. IgM is the first antibody produced in a primary response; IgA is dominant in mucosal secretions.

31. B - SCID is defined by severe combined cellular (T cell) and humoral (B cell) immunodeficiency. SCID is a medical emergency; untreated infants typically die within the first 2 years from overwhelming infections. The combined cellular + humoral deficiency distinguishes it from isolated B cell or T cell deficiencies.

32. B - X-linked SCID (the most common SCID) is caused by IL2RG mutations (common gamma chain, gamma-c). Gamma-c is shared by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Loss of gamma-c blocks T and NK cell development; B cells are present but non-functional (TB-NK-SCID phenotype).

33. B - ADA deficiency is autosomal recessive SCID. ADA normally converts adenosine and deoxyadenosine to inosine. Without ADA, deoxyadenosine and dATP accumulate → toxic to lymphocytes → profound T, B, and NK cell deficiency. ADA deficiency was the first condition treated by gene therapy (1990).

34. B - DiGeorge syndrome (22q11.2 deletion) causes thymic aplasia/hypoplasia → absent or markedly reduced T cell maturation and output. B cells are present, but without T cell help, humoral immunity is also impaired. Associated features: cardiac defects, hypoparathyroidism (hypocalcemia), palatal abnormalities (CATCH-22).

35. C - CGD is caused by mutations in NADPH oxidase components (most commonly X-linked CYBB encoding gp91-phox). Phagocytes ingest organisms normally but cannot produce the respiratory burst → cannot kill catalase-positive organisms (Staphylococcus aureus, Aspergillus, Burkholderia). Granulomas form because organisms cannot be cleared. Nitroblue tetrazolium (NBT) test is used for diagnosis.

36. B - Bruton's agammaglobulinemia: BTK is required for B cell development beyond the pro-B cell stage. Absent BTK → complete block in B cell maturation → absent mature B cells → absent immunoglobulins of all classes. T cells are completely normal. Boys present at ~6 months when maternal IgG wanes, with recurrent bacterial sinopulmonary infections.

37. C - The clinical picture (recurrent encapsulated bacterial infections, very low serum Ig, normal resistance to viruses and fungi, onset at ~6 months after maternal Ab wanes) is classic for X-linked agammaglobulinemia. SCID presents with both bacterial and opportunistic (PCP, Candida, CMV) infections and failure to thrive.

38. B - Hereditary angioedema (HAE) types I and II are caused by C1-INH deficiency or dysfunction. Without C1-INH, the classical complement pathway is unregulated → excessive bradykinin production → episodic angioedema of face, extremities, GI tract, larynx. Laryngeal edema can be fatal. C1-INH concentrate, icatibant, or lanadelumab are used for treatment.

39. B - The ABO gene on chromosome 9q34 encodes a glycosyltransferase that adds specific sugar residues to the H antigen on RBC surface. A allele adds N-acetylgalactosamine (group A antigen); B allele adds galactose (group B antigen); O allele is non-functional (no additional sugar added).

40. B - Group O: No ABO glycosyltransferase activity → RBCs carry only the H antigen (no A or B antigens). Serum contains both anti-A and anti-B isohemagglutinins (IgM). Group O individuals are universal donors for RBCs but can only receive group O blood.

41. B - Rh incompatibility is the most clinically significant cause of severe HDN. Anti-D IgG antibodies cross the placenta and destroy fetal RBCs. The ABO system can cause mild HDN (usually in group O mothers with group A or B babies) but is typically mild because ABO antigens are also expressed on other tissues, diluting antibody attack.

42. B - First pregnancy: First exposure to Rh-D antigen → primary immune response → mainly IgM (does not cross placenta) + development of memory B cells + some IgG. No significant fetal damage. Subsequent pregnancy with Rh+ fetus: Memory B cells rapidly produce high-titer IgG anti-D → crosses placenta → severe HDN. Anti-D prophylaxis (Rhogam) prevents sensitization.

43. A - Wiskott-Aldrich syndrome: X-linked (WAS gene encoding WASP protein). Classic triad: thrombocytopenia (small abnormal platelets), eczema, recurrent infections (combined T and B cell immunodeficiency). Autoimmune complications and lymphoma are also features.

44. B - The liability/threshold model (Falconer model): All factors contributing to disease (genetic variants + environmental) combine to give each individual a "liability." This is normally distributed. Individuals above the threshold become affected. The distribution of liability in relatives of affected individuals is shifted toward higher values.

45. B - In multifactorial inheritance, risk to relatives increases with more affected family members (because each affected relative increases the probability that the family carries more susceptibility alleles) and with greater severity of the index case. This contrasts with Mendelian disorders where recurrence risk is fixed.

46. C - Neural tube defects (NTDs - anencephaly, spina bifida, encephalocele) are the classic examples of multifactorial disorders where genes and environment (folate deficiency, antiepileptic drugs, maternal diabetes) both contribute. Other examples: cleft lip/palate, congenital heart disease, pyloric stenosis, congenital hip dislocation.

47. B - The empiric rule: sibling recurrence risk ≈ √(population incidence). √(1/400) = 1/20 = 5%. This is an approximation; actual empiric risks are determined from population studies, not this formula exactly - but it illustrates why sibling risk is much higher than population risk but much lower than the 25-50% of Mendelian disorders.

48. B - The WHO and national guidelines recommend periconceptional folic acid supplementation (400 mcg/day for general population; 4-5 mg/day for women with a previous affected child). Studies show 70-75% reduction in recurrence risk. Folic acid is the effective constituent of multivitamins.

49. C - MZ twin concordance for T1DM is approximately 50% (ranges 30-65% in studies). This is significantly less than 100%, confirming that environmental factors are required in addition to genetic susceptibility (not purely genetic). DZ concordance is ~12%.

50. B - The HLA region on chromosome 6p21 contributes approximately 50% of the genetic susceptibility to T1DM. Specifically, HLA-DR3 and/or DR4 are present in ~95% of T1DM patients (vs. ~50% of controls). The DQ beta 57 residue (aspartate = protective; other amino acids = susceptible) is particularly important.

51. B - T1DM is an autoimmune disease. Autoreactive T cells (and autoantibodies to islet antigens: GAD65, IA-2, insulin, ZnT8) destroy beta cells. The disease process begins years before clinical presentation. Environmental triggers (viral infections, gut microbiome, diet) likely interact with genetic predisposition.

52. C - Approximately 95% of T1DM patients carry HLA-DR3 and/or DR4 (compared to ~50% of the general population). The specific DQ alleles (DQB10302 with DR4; DQA10501-DQB1*0201 with DR3) confer the highest risk. The DR2 haplotype is protective.

53. A - The INS VNTR locus: Short (class I) repeats are associated with LOWER insulin expression in the fetal thymus → less central tolerance to insulin → higher T1DM risk. Long (class III) repeats → higher thymic insulin expression → better central tolerance → protection from T1DM. This illustrates the key concept of central immune tolerance to self-antigens.

54. B - MZ twin concordance for T2DM is >60-90% in most studies, substantially higher than T1DM concordance (~50%). This indicates T2DM has a stronger heritable component, though the genetic architecture is complex (many susceptibility loci, each with small effect). Environmental factors (obesity, sedentary lifestyle) are also critical.

55. B - MODY (Maturity-Onset Diabetes of the Young) encompasses several monogenic, autosomal dominant forms of diabetes. They present in non-obese young people (<25 years) and do not initially require insulin. MODY2 (glucokinase gene) causes mild fasting hyperglycemia; MODY3 (HNF1A) is most common and responds to sulfonylureas.

56. B - Gestational diabetes affects ~10% of pregnancies. After delivery, glucose tolerance returns to normal in most women, but they carry a significantly increased lifetime risk of developing T2DM (~50% within 10 years). During pregnancy, risks include fetal macrosomia, neonatal hypoglycemia, and increased cesarean section rate.

57. B - PKU was the first human genetic disorder shown to be caused by a specific enzyme deficiency (by Jervis, 1953). Phenylalanine hydroxylase (PAH) converts phenylalanine to tyrosine. Deficiency leads to phenylalanine accumulation → phenylpyruvic acid in urine (hence "phenylketo-uria") + tyrosine deficiency → reduced melanin.

58. B - Untreated PKU: high phenylalanine and phenylpyruvate are toxic to the developing brain. Clinical features: severe intellectual disability (IQ often <50), seizures, hyperactivity, eczema, fair hair and blue eyes (reduced melanin), and a "mousy" or "musty" urine odor from phenylacetic acid. Early dietary treatment prevents intellectual disability.

59. B - Treatment: Phenylalanine-restricted diet (phenylalanine is an essential amino acid - cannot eliminate completely; must provide the minimum amount for protein synthesis while keeping blood Phe levels <360 μmol/L). Regular blood Phe monitoring guides dietary adjustment. Dietary restriction was traditionally maintained throughout life, especially for females during pregnancy (maternal PKU).

60. B - Alkaptonuria (deficiency of homogentisate 1,2-dioxygenase): homogentisic acid accumulates → excreted in urine, which turns dark brown-black on standing (especially in alkaline conditions, e.g., nappies). Ochronosis = dark pigmentation of cartilage, tendons, sclerae. Arthropathy develops in middle age.

61. B - MSUD: The branched-chain alpha-keto acid dehydrogenase (BCKAD) complex decarboxylates the keto acid derivatives of leucine, isoleucine, and valine. The complex has four subunits (E1alpha, E1beta, E2, E3). Mutations in any subunit cause MSUD. The E3 subunit is shared with pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase.

62. B - The three branched-chain amino acids (BCAAs) that accumulate in MSUD are leucine, isoleucine, and valine (the "LIV" amino acids). Leucine is the most neurotoxic and is primarily responsible for the acute neurological deterioration. The corresponding keto acids (alpha-KIV, alpha-KMV, alpha-KIV) are also elevated.

63. B - MSUD presents in the first week of life: poor feeding, vomiting, then alternating hypotonia and hypertonia (cerebral edema), followed by seizures and coma if untreated. The characteristic maple-syrup odor of urine (due to sotolone, derived from leucine catabolites) is the diagnostic clue. Prognosis is good with early dietary restriction.

64. C - Both homocystinuria and Marfan syndrome share: tall stature, arachnodactyly, pectus deformity, scoliosis, lens dislocation. Features UNIQUE to homocystinuria: intellectual disability (~50% of untreated cases), thromboembolic events (arterial and venous - due to homocysteine damaging endothelium and promoting platelet aggregation). Marfan syndrome does NOT cause intellectual disability or thrombophilia.

65. C - The cyanide-nitroprusside (Brand's) test: a positive result (magenta/purple color) indicates elevated urinary sulfhydryl compounds, particularly homocysteine/homocystine. It screens for homocystinuria. This test is semi-quantitative; confirmation is by plasma homocysteine measurement and CBS gene analysis. PKU is screened by the Guthrie test (bacterial inhibition assay) or tandem MS.

66. B - The urea cycle has 5 enzymatic steps: (1) CPS-I (mitochondria) - carbamoyl phosphate synthesis; (2) OTC (mitochondria) - citrulline formation; (3) Argininosuccinate synthetase (cytoplasm) - argininosuccinate formation; (4) Argininosuccinate lyase (cytoplasm) - arginine formation; (5) Arginase (cytoplasm) - urea release + ornithine regeneration.

67. B - OTC deficiency is X-linked (Xp21.1); it is the most common urea cycle disorder. Hemizygous males are severely affected (neonatal hyperammonemic coma). Heterozygous females are carriers but may have variable expression from mild to severe (due to random X-inactivation in hepatocytes). All other urea cycle disorders are autosomal recessive.

68. B - The biochemical hallmark of all urea cycle disorders is hyperammonemia (elevated plasma ammonia). Ammonia is toxic to the CNS → cerebral edema, encephalopathy, coma, and death if untreated. Normal plasma ammonia is 15-45 μmol/L; in urea cycle disorders, levels can exceed 1000 μmol/L.

69. C - Undetectable citrulline indicates a block BEFORE citrulline synthesis: either CPS-I deficiency (cannot form carbamoyl phosphate) or OTC deficiency (cannot use carbamoyl phosphate + ornithine to make citrulline). Both present identically biochemically. OTC is more common and X-linked. CPS-I is autosomal recessive. The distinction requires enzyme assay or molecular testing.

70. B - Citrullinemia type I (ASS1 deficiency): autosomal recessive. Citrulline cannot be converted to argininosuccinate → markedly elevated plasma citrulline (often >1000 μmol/L, vs. normal 10-45 μmol/L). Presents with neonatal hyperammonemia. Treatment: protein restriction, arginine supplementation, nitrogen scavengers (sodium benzoate, sodium phenylacetate), citrulline restriction.

71. B - The fundamental classification in gene therapy is: (1) Somatic gene therapy - modifies non-reproductive cells (muscle, liver, blood cells); changes are not heritable. (2) Germline gene therapy - modifies eggs, sperm, or early embryos; changes would be heritable. Human germline gene therapy remains highly controversial and is not approved in most jurisdictions.

72. B - Viral vectors used in gene therapy: adeno-associated viruses (AAV), retroviruses/lentiviruses (stably integrate into genome), adenoviruses. Non-viral vectors: liposomes, nanoparticles, electroporation, naked plasmid DNA. AAV is currently the most widely used vector in approved gene therapies (e.g., Luxturna for RPE65 mutations, Zolgensma for SMA).

73. B - Retroviral and lentiviral vectors integrate randomly into the host genome. If insertion occurs near a proto-oncogene promoter, it may dysregulate expression. This risk materialized in X-linked SCID gene therapy trials (2002-2003), where retroviral insertion near the LMO2 oncogene caused T-cell leukemia in several patients. Self-inactivating (SIN) vectors reduce this risk.

74. C - The first gene therapy trial was in 1990 for ADA-SCID (Blaese and Anderson). T lymphocytes from a 4-year-old girl were transduced ex vivo with retroviral vector carrying the ADA gene and reinfused. This was a proof-of-concept but achieved partial success. Today, ex vivo HSC gene therapy for ADA-SCID (Strimvelis) is approved in Europe.

75. B - Ex vivo gene therapy: cells (typically HSCs, T cells, or other autologous cells) are harvested, modified in the laboratory using viral or non-viral vectors, and then reinfused into the patient. This allows quality control and selection of transduced cells. In vivo gene therapy delivers the vector directly to the patient (e.g., intravitreal injection of AAV for RPE65 disease).

76. B - Antisense oligonucleotides (ASOs) are short synthetic single-stranded DNA or RNA sequences complementary to target mRNA. They bind via Watson-Crick base pairing → sterically block ribosome translation, trigger RNase H-mediated mRNA degradation, or modulate splicing (exon skipping - as in eteplirsen for DMD). They are not gene replacement therapy.

77. D - Gene therapy approaches for cancer include: (a) tumor suppressor gene replacement (TP53 restoration); (b) immunotherapy (CAR-T cells, cancer vaccines, checkpoint modulation); (c) oncolytic viruses; (d) RNA interference / antisense to silence oncogenes; (e) suicide gene therapy; (f) anti-angiogenesis (suppressing VEGF). All four listed options (A, B, C, D) are valid cancer gene therapy approaches.

78. B - AAV advantages: infects both dividing and non-dividing cells (important for targeting neurons, muscle, liver); low pathogenicity (no known human disease); low immunogenicity; can persist as episomes (non-integrating, reducing insertional mutagenesis risk); multiple serotypes allow tissue targeting. Disadvantage: limited cargo capacity (~4.7 kb).

79. B - The core ethical objection to human germline editing: modifications made to germ cells or embryos will be inherited by all future generations of descendants, who cannot consent. Additionally, unintended off-target mutations could be propagated, and population-level effects on genetic diversity are unpredictable. This distinguishes it from somatic gene therapy, which affects only the treated individual.

80. B - CRISPR-Cas9: The guide RNA (gRNA, ~20 nt) is complementary to the target DNA sequence. The gRNA-Cas9 complex binds the target, and Cas9 makes a double-strand break. The cell repairs the break via NHEJ (introducing insertions/deletions - gene disruption) or HDR (precise editing using a donor template - gene correction). CRISPR is transforming gene therapy, with approved therapies now available (e.g., Casgevy for sickle cell/beta-thalassemia, 2023).

81. B - Eugenics (Greek: "well-born") was coined by Francis Galton in 1883. Positive eugenics: encouraging "fit" individuals to reproduce. Negative eugenics: discouraging or preventing "unfit" individuals from reproducing. The Nazi race hygiene programs represent the most extreme and horrific application of eugenics.

82. B - Negative eugenics historically included compulsory sterilization laws (e.g., in the US, Sweden, Nazi Germany), institutionalization, and restrictions on marriage of people with genetic diseases, intellectual disabilities, or psychiatric conditions. These programs violated fundamental human rights and are universally condemned.

83. B - The "dysgenic" concern: without natural selection weeding out deleterious alleles, medical interventions (treating genetic diseases, enabling reproduction by affected individuals) could theoretically increase the frequency of harmful alleles in the gene pool over generations. However, since most genetic disease alleles are recessive and maintained by heterozygote carriers, the actual rate of allele frequency change is very slow.

84. B - Modern genetic counseling is built on the principle of non-directiveness and respect for individual autonomy. It provides accurate, unbiased information about risks and options (including prenatal diagnosis, PGD, adoption, not having children, or accepting the risk) without advising what reproductive decision to make. This is the antithesis of eugenics.

85. B - The core principle of genetic counseling (as defined by the ASHG): non-directive counseling - providing information and support, not making decisions for families. The genetic counselor's role is to inform, not to direct. Reproductive decisions belong to the individual or couple.

86. B - The "future generations" argument against germline editing parallels the core objection to eugenics: we cannot know what heritable changes we are making to future descendants who have no say in the matter. Additionally, concerns exist about population-level effects, exacerbation of inequality (only wealthy individuals accessing "designer" genes), and slippery slope toward non-therapeutic enhancements.

87. B - CAIS karyotype 46,XY + female phenotype: The Wolffian (mesonephric) ducts regress (because testosterone cannot act); testes produce AMH → Mullerian (paramesonephric) ducts regress → no uterus or fallopian tubes. External genitalia are female (androgens cannot virilize). Testes present in inguinal canal or labia majora.

88. B - CAIS is caused by loss-of-function mutations in the AR gene on Xq11-12. The androgen receptor cannot bind testosterone or DHT (or cannot translocate to the nucleus, or cannot activate transcription). The XY individual is insensitive to androgens → completely female external phenotype despite male gonads and male circulating testosterone levels.

89. B - In CAIS, testosterone is synthesized normally by the testes and is at normal or elevated male-range levels. However, because the androgen receptor is non-functional, testosterone cannot exert its effects. Testosterone is peripherally aromatized to estradiol by the testes and adipose tissue, providing the feminizing effect that drives puberty (breast development, female fat distribution) in CAIS women.

90. B - PAIS: Partial AR function → partial androgen response → ambiguous genitalia at birth (variable degree of phallic development, labioscrotal fusion, hypospadias). Clinical spectrum is wide. Some PAIS individuals are raised female; others male. Management is complex and requires multidisciplinary DSD teams.

91. B - 5-alpha reductase type 2 (SRD5A2) converts testosterone → dihydrotestosterone (DHT) in the external genitalia and prostate. DHT is required for male external genitalia development (virilization). Without DHT: 46,XY infants have ambiguous or female-appearing external genitalia at birth (testosterone-dependent Wolffian structures - epididymis, vas deferens, seminal vesicles - develop normally). At puberty, high testosterone causes virilization → phallic enlargement, deepened voice, increased muscle mass. Common in the Dominican Republic.

92. C - 21-hydroxylase (CYP21A2) deficiency accounts for >90% of all CAH cases. The CYP21A2 gene is on chromosome 6p21.3, adjacent to HLA. Autosomal recessive inheritance. The gene has a nearby pseudogene (CYP21A1P) that causes most mutations via gene conversion.

93. B - 21-hydroxylase converts progesterone → 11-deoxycorticosterone (in the mineralocorticoid pathway) and 17-hydroxyprogesterone → 11-deoxycortisol (in the glucocorticoid pathway). Deficiency blocks both cortisol AND aldosterone synthesis. Precursors (17-OHP, DHEA, androstenedione) accumulate → shunted to androgen synthesis → adrenal androgen excess.

94. B - Classic salt-wasting CAH (most severe form, ~75% of classic CAH): Both cortisol AND aldosterone deficient. 46,XX females: virilized external genitalia (enlarged clitoris, labioscrotal fusion - "ambiguous genitalia"). 46,XY males: appear normal at birth. Both sexes: adrenal crisis at 1-4 weeks of life with hyponatremia, hyperkalemia, hypotension, hypoglycemia. Non-salt-wasting (simple virilizing) form: aldosterone production is sufficient.

95. C - CAH (21-hydroxylase deficiency) follows autosomal recessive inheritance. Both parents are typically asymptomatic carriers. Risk to each child: 1 in 4. The CYP21A2 gene is close to HLA on chromosome 6 → linkage disequilibrium means certain HLA haplotypes are associated with specific CYP21A2 mutations.

96. B - Prenatal dexamethasone treatment: dexamethasone (a fluorinated GC) crosses the placenta and suppresses fetal pituitary ACTH → reduces adrenal androgen production → prevents virilization of affected female fetus. Must start by 6-7 weeks of gestation (before external genitalia differentiation). Only affected females benefit; treatment is stopped if fetus is male or unaffected (confirmed by prenatal diagnosis from CVS or amniocentesis).

97. A - Long-term CAH management: Glucocorticoid replacement (hydrocortisone 3 times daily in children; longer-acting agents in adults) suppresses ACTH → reduces adrenal androgen overproduction. Mineralocorticoid replacement (fludrocortisone) for salt-wasting forms. Regular monitoring of growth, bone age, 17-OHP, and androgens. Stress dosing (3x normal) during illness, surgery, or trauma.

98. B - 11-beta-hydroxylase deficiency (CYP11B1): blocks conversion of 11-deoxycortisol → cortisol AND 11-deoxycorticosterone (DOC) → corticosterone. DOC accumulates → potent mineralocorticoid effect → sodium retention, hypertension, hypokalemia. ACTH excess drives androgen overproduction → virilization. Presents with hypertension + virilization (contrast: 21-OHD is hypoTENSIVE in salt-wasting form).

99. B - The key diagnostic clues: (1) 46,XX infant with ambiguous genitalia; (2) markedly elevated 17-OHP on ACTH stimulation (17-OHP is the substrate just before the 21-hydroxylase block); (3) salt-wasting crisis (hyponatremia + hyperkalemia). This is pathognomonic for classic salt-wasting 21-hydroxylase deficiency CAH. CAIS presents in a 46,XY infant; 5-alpha reductase deficiency presents in a 46,XY infant without elevated 17-OHP.

100. B - In CAIS, the testes produce estradiol (via aromatase) which drives feminizing puberty (breast development, female body habitus). Early gonadectomy (before puberty) was traditionally performed, but this deprives the patient of natural estrogen-driven puberty. Current consensus: delay gonadectomy until after puberty is complete (age ~16-20). The lifetime risk of malignancy in CAIS testes is ~2-3% (gonadoblastoma, dysgerminoma) - lower than previously thought - and typically not life-threatening if monitored.

Total: 100 Questions | 8 Topic Areas Covered

Topic breakdown:

Q1-15: Cancer Genetics (15 Qs)
Q16-30: Immunogenetics - Innate & Acquired Immunity (15 Qs)
Q31-43: Inherited Immunodeficiency & Blood Groups (13 Qs)
Q44-56: Multifactorial Inheritance & Diabetes (13 Qs)
Q57-70: Amino Acid Disorders, BCAA, Urea Cycle (14 Qs)
Q71-80: Gene Therapy (10 Qs)
Q81-86: Eugenics & Dysgenics (6 Qs)
Q87-100: Androgen Insensitivity & CAH (14 Qs)

All questions are referenced to Emery's Elements of Medical Genetics and Genomics. Best of luck in your finals!

I have my mbbs final exam and it’s going to be an mcq exam I want you to creat 100 questions from the topics make sure they are theoretical as well as clinically based questions take reference from Signal Transduction: Principles, Pathways, and Processes 1st Edition by Lewis Cantley, Tony Hunter, Richard Sever, Jeremy Thorner; 1. Diversity of signaling cascades: calcium signaling, redox signaling, lipid signaling and signaling by gases. 1. Nuclear receptors, signaling cross talk and regulation of gene expression: ultimate target for signal transduction; (Part 1) 2. Nuclear receptors, signaling cross talk and regulation of gene expression: ultimate target for signal transduction; (Part 2) 3. Cell death, apoptosis signaling during development and disease Signaling pathways in cancer cells, oncogenes, tumor suppressors, anti-EGFR cell signaling-based therapeutic strategies (part 1) Signaling pathways in cancer cells, oncogenes, tumor suppressors, anti-EGFR cell signaling-based therapeutic strategies; (Part 2 Signaling during inflammation, innate immunity and lymphocyte activation, TNF, TCR and TLR signaling pathways (Part 1) Signaling during inflammation, innate immunity and lymphocyte activation, TNF, TCR and TLR signaling pathways (Part 2)

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Create a Word document with all 200 MCQs from the three exam sets you've received

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