60 USMLE Step 1 Biochemistry Practice Questions with Explanations

We introduce the 60 high yield USMLE Step 1 and NBME CBSE style biochemistry questions and answers with explanations.
Good luck!

1. A 22-year-old man of Mediterranean descent presents with jaundice and dark urine a few days after taking an antibiotic for a urinary tract infection. He reports a history of similar episodes after eating fava beans. Laboratory analysis shows anemia and the presence of Heinz bodies in many erythrocytes. Which of the following is the most likely cause of this patient's condition?
   A. Glucose-6-phosphate dehydrogenase deficiency
   B. Pyruvate kinase deficiency
   C. Hereditary spherocytosis
   D. Autoimmune hemolytic anemia
   E. Aplastic anemia

   Explanation: The correct answer is A. This patient’s intermittent hemolysis triggered by oxidative stress (sulfa drugs, fava beans) is characteristic of glucose-6-phosphate dehydrogenase (G6PD) deficiency, which leads to impaired NADPH production and inability to keep glutathione reduced. RBCs become susceptible to oxidative damage, causing hemoglobin to precipitate as Heinz bodies that are removed by spleen macrophages (bite cells). Episodes self-resolve as older RBCs are destroyed and replaced.
   Choice B: Pyruvate kinase deficiency causes congenital hemolytic anemia from birth, not episodic oxidative hemolysis.
   Choice C: Hereditary spherocytosis causes chronic hemolysis with spherocytes and splenomegaly, not episodic crises due to oxidative stress.
   Choice D: Autoimmune hemolytic anemia (e.g., drug-induced) usually has a positive Coombs test and no Heinz bodies or specific triggers like fava beans.
   Choice E: Aplastic anemia leads to pancytopenia (bone marrow failure) rather than episodic hemolysis, and it would not produce Heinz bodies.

2. A 1-week-old newborn boy is evaluated for persistent jaundice and pallor. He was born at term to healthy parents. Laboratory testing shows hemolytic anemia and elevated 2,3-bisphosphoglycerate in his red blood cells. Further evaluation reveals splenomegaly. Which of the following is the most likely cause of this infant’s condition?
   A. Glucose-6-phosphate dehydrogenase deficiency
   B. Hereditary spherocytosis
   C. Beta-thalassemia major
   D. Pyruvate kinase deficiency
   E. Sickle cell disease

   Explanation: The correct answer is D. Pyruvate kinase deficiency (autosomal recessive) causes chronic hemolytic anemia in newborns due to an inability to generate sufficient ATP in red blood cells. The resulting membrane rigidity leads to extravascular hemolysis (splenic destruction, hence splenomegaly). The block in glycolysis causes increased 2,3-BPG, which shifts the hemoglobin O₂ curve rightward (decreasing O₂ affinity). Unlike G6PD deficiency, this hemolysis is ongoing from birth (not episodic).
   Choice A: G6PD deficiency causes episodic hemolysis with oxidative triggers, not persistent neonatal hemolysis.
   Choice B: Hereditary spherocytosis (membrane skeleton defect) causes hemolysis and splenomegaly, but typically presents with spherocytes and positive osmotic fragility test; it’s not a glycolytic enzyme issue.
   Choice C: Beta-thalassemia major causes severe microcytic anemia in infancy with transfusion dependence and abnormal hemoglobin electrophoresis, not the enzyme-related hemolysis described here.
   Choice E: Sickle cell disease (β-globin mutation) usually presents after 6 months (when fetal hemoglobin wanes) with sickled cells and vaso-occlusive crises, not neonatal hemolysis due to an enzyme defect.

3. A 3-month-old infant is brought to the ED due to seizures. The baby has hepatomegaly and doll-like facial features. Labs show severe hypoglycemia with elevated lactate and uric acid. A liver biopsy reveals excessive glycogen with normal structure. Which of the following is the most likely cause of this infant’s condition?
   A. Pompe disease (Type II glycogen storage disease)
   B. Cori disease (Type III glycogen storage disease)
   C. Von Gierke disease (Type I glycogen storage disease)
   D. McArdle disease (Type V glycogen storage disease)
   E. Hereditary fructose intolerance

   Explanation: The correct answer is C. Von Gierke disease (Type I GSD) is due to a glucose-6-phosphatase deficiency in the liver, leading to impaired glycogenolysis and gluconeogenesis. Infants have severe fasting hypoglycemia, lactic acidosis (Cori cycle is impaired), hyperuricemia, hyperlipidemia, and massive hepatomegaly from glycogen buildup (with normal glycogen structure).
   Choice A: Pompe disease (lysosomal acid maltase deficiency) causes cardiomegaly, hypotonia, and early death, not fasting hypoglycemia or lactic acidosis.
   Choice B: Cori disease (debranching enzyme deficiency) causes milder hypoglycemia and no lactic acidosis; glycogen has short outer branches (limit dextrin-like).
   Choice D: McArdle disease (muscle glycogen phosphorylase deficiency) presents with exercise-induced cramps and myoglobinuria in adolescence, no hepatomegaly or fasting hypoglycemia.
   Choice E: Hereditary fructose intolerance (aldolase B deficiency) presents after fructose introduction (juice, foods) with hypoglycemia and liver failure, not from birth with glycogen accumulation.

4. A 4-month-old infant has poor feeding, muscle weakness, and failure to thrive. Exam reveals marked cardiomegaly, hypotonia, and mild hepatomegaly. Lab shows elevated creatine kinase. Which of the following is the most likely underlying cause of this infant’s condition?
   A. Pompe disease (lysosomal acid maltase deficiency)
   B. Von Gierke disease (glucose-6-phosphatase deficiency)
   C. Primary carnitine deficiency
   D. McArdle disease (muscle glycogen phosphorylase deficiency)
   E. Niemann-Pick disease

   Explanation: The correct answer is A. Pompe disease (Type II GSD) is caused by a deficiency of lysosomal acid α-1,4-glucosidase (acid maltase). Infants present with cardiomegaly, hypotonia, feeding difficulties, and hepatomegaly due to accumulation of glycogen in lysosomes (especially in heart and muscle). Pompe is often fatal in infancy due to heart failure; notably, it does not cause hypoglycemia (unlike other GSDs).
   Choice B: Von Gierke disease (Type I GSD) causes severe hypoglycemia and lactic acidosis with hepatomegaly, but no cardiomegaly or such early hypotonia.
   Choice C: Primary carnitine deficiency can cause hypotonia and cardiomyopathy in infancy, but it’s due to an inability to utilize fats (hypoketotic hypoglycemia) rather than glycogen accumulation.
   Choice D: McArdle disease presents in adolescence with muscle cramps during exercise and myoglobinuria, not infantile cardiomyopathy.
   Choice E: Niemann-Pick disease (sphingomyelinase deficiency) causes hepatosplenomegaly, neurodegeneration, and a cherry-red macula, not isolated cardiomegaly with muscle weakness in an infant.

5. A 20-year-old man gets muscle cramps and dark urine after intense exercise like sprinting. He notes the cramps improve if he rests briefly then continues exercise more slowly. His blood glucose remains normal during exercise. Which of the following is the most likely explanation for his symptoms?
   A. Myasthenia gravis
   B. Carnitine palmitoyltransferase II deficiency
   C. McArdle disease (muscle glycogen phosphorylase deficiency)
   D. Peripheral arterial disease (intermittent claudication)
   E. Pompe disease (Type II glycogen storage disease)

   Explanation: The correct answer is C. McArdle disease (Type V GSD) is caused by a muscle glycogen phosphorylase deficiency. Affected individuals have an inability to break down muscle glycogen during anaerobic exercise, leading to exercise intolerance, muscle cramps, and myoglobinuria (dark urine) after strenuous activity. The “second-wind” phenomenon (symptom improvement after a brief rest) occurs as the muscles switch to blood glucose and fatty acids for energy. Blood glucose is usually normal (hepatic glycogenolysis is intact).
   Choice A: Myasthenia gravis causes muscle fatigue (especially in eyes/throat) that worsens with use, but no muscle pain or myoglobinuria, and it improves with rest (not second-wind).
   Choice B: CPT II deficiency (a fatty acid oxidation defect) can cause exercise-induced muscle pain and myoglobinuria, but typically with prolonged exercise or fasting, plus hypoketotic hypoglycemia—features not seen here.
   Choice D: PAD (claudication) occurs in older individuals with atherosclerosis; it causes exercise-induced pain due to poor blood flow, but it’s unlikely in a young man and wouldn’t cause myoglobinuria.
   Choice E: Pompe disease presents in infancy with cardiomyopathy and severe muscle weakness, not isolated exercise intolerance in adulthood.

6. A 7-month-old infant, healthy while exclusively breastfed, becomes lethargic and vomits after being weaned to fruit juices. He has jaundice, hepatomegaly, and seizures due to hypoglycemia. Which enzyme deficiency is the most likely cause of his condition?
   A. Fructokinase deficiency (essential fructosuria)
   B. Aldolase B deficiency (hereditary fructose intolerance)
   C. Galactose-1-phosphate uridyltransferase deficiency (classic galactosemia)
   D. Glucose-6-phosphatase deficiency (Von Gierke disease)
   E. Fructose-1,6-bisphosphatase deficiency

   Explanation: The correct answer is B. Hereditary fructose intolerance is caused by an aldolase B deficiency, leading to an accumulation of fructose-1-phosphate in the liver after ingesting fructose or sucrose. This traps phosphate and inhibits gluconeogenesis and glycogenolysis, causing severe hypoglycemia, vomiting, jaundice, hepatomegaly, and seizures after fructose intake. Symptoms typically appear after introduction of fruits, juice, or sucrose (as in this weaning scenario). Treatment is to eliminate fructose (and sucrose) from the diet.
   Choice A: Essential fructosuria (fructokinase deficiency) is benign, causing asymptomatic fructose in urine but no hypoglycemia or organ damage.
   Choice C: Classic galactosemia (GALT deficiency) presents in newborns (soon after milk feeding) with vomiting, jaundice, hepatomegaly, and cataracts. It’s due to galactose metabolism, not fructose, and occurs earlier.
   Choice D: Von Gierke disease causes severe fasting hypoglycemia and lactic acidosis from birth, not specifically triggered by fructose introduction.
   Choice E: Fructose-1,6-bisphosphatase deficiency impairs gluconeogenesis and can cause fasting hypoglycemia and lactic acidosis, but it usually presents with fasting intolerance (not specifically after fructose intake) and is much rarer than aldolase B deficiency.

7. A 5-day-old newborn has vomiting, jaundice, and lethargy after starting formula feeding. Exam shows hepatomegaly and bilateral cataracts. Labs reveal hypoglycemia and a positive test for reducing substances in the urine. She develops E. coli sepsis. Which enzyme deficiency is the most likely cause of this infant’s condition?
   A. Galactose-1-phosphate uridyltransferase deficiency
   B. Galactokinase deficiency
   C. Aldolase B deficiency
   D. Glucose-6-phosphatase deficiency
   E. Ornithine transcarbamylase deficiency

   Explanation: The correct answer is A. Classic galactosemia is caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT). Newborns present shortly after initiating feeds (breast milk or formula contains lactose → galactose) with jaundice, vomiting, hepatomegaly, hypoglycemia, and cataracts. Accumulation of galactose-1-P in liver and other tissues causes damage. A classic association is neonatal E. coli sepsis in untreated galactosemia. Treatment is eliminating galactose (lactose) from the diet.
   Choice B: Galactokinase deficiency is a milder disorder causing cataracts but no liver failure or severe hypoglycemia.
   Choice C: Aldolase B deficiency (hereditary fructose intolerance) presents after fructose is introduced (later in infancy) with liver failure and hypoglycemia, not in the first week of life on milk.
   Choice D: Glucose-6-phosphatase deficiency (Von Gierke) causes severe fasting hypoglycemia and lactic acidosis, but not cataracts or issues specifically with milk feeding.
   Choice E: Ornithine transcarbamylase (OTC) deficiency causes hyperammonemia in neonates (especially boys), with no hypoglycemia or cataracts, since it’s a urea cycle disorder.

8. The parents of a 2-year-old girl are concerned about her developmental delay and a peculiar “musty” body odor. The child has fair skin and hair, blue eyes, eczema, and has never had newborn screening. Which enzymatic defect is the most likely cause of this child’s condition?
   A. Cystathionine synthase deficiency (homocystinuria)
   B. Phenylalanine hydroxylase deficiency (phenylketonuria)
   C. Homogentisate oxidase deficiency (alkaptonuria)
   D. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease)
   E. Tyrosinase deficiency (oculocutaneous albinism)

   Explanation: The correct answer is B. Phenylketonuria (PKU) is caused by a deficiency of phenylalanine hydroxylase, resulting in an inability to convert phenylalanine to tyrosine. The buildup of phenylalanine leads to intellectual disability, seizures, eczema, a musty/mousy odor, and fair skin/hair (because tyrosine is needed for melanin). Newborn screening typically detects PKU early, so dietary restriction of phenylalanine (and tyrosine supplementation) can prevent these symptoms.
   Choice A: Homocystinuria (cystathionine synthase deficiency) causes Marfanoid habitus, downward lens dislocation, intellectual disability, and thrombosis, but not a musty odor or fair complexion.
   Choice C: Alkaptonuria (homogentisate oxidase deficiency) causes dark urine on standing and bluish-black connective tissue (ochronosis) with arthropathy in adulthood; it does not cause infant developmental delay or odor.
   Choice D: Maple syrup urine disease (BCKD complex deficiency) presents in neonates with poor feeding, vomiting, and a maple syrup odor to urine; it does not fit a 2-year-old with musty odor.
   Choice E: Oculocutaneous albinism (tyrosinase defect) causes lack of melanin and fair features, but no musty odor or developmental delay—those features point specifically to PKU.

9. A 15-year-old boy has progressive vision problems and learning difficulties. He is tall and lanky with long limbs, pectus excavatum, and joint hyperflexibility. His lenses are dislocated downward. He also has pale skin with a livedo reticularis rash and a history of a thrombotic stroke at age 14. Which of the following is the most likely diagnosis?
   A. Marfan syndrome (fibrillin-1 mutation)
   B. Ehlers-Danlos syndrome (collagen defect)
   C. Phenylketonuria
   D. Vitamin B6 (pyridoxine) deficiency
   E. Homocystinuria (cystathionine synthase deficiency)

   Explanation: The correct answer is E. Homocystinuria (usually due to cystathionine synthase deficiency) causes a Marfan-like habitus with intellectual disability and thrombosis. Lens subluxation in homocystinuria is typically downward (versus upward in Marfan). High homocysteine levels cause endothelial damage and a hypercoagulable state (leading to strokes at young age). Treatment includes pyridoxine (B6) supplementation and methionine restriction.
   Choice A: Marfan syndrome causes a similar body habitus and lens subluxation (upward), but it does not cause intellectual disability or early thrombosis.
   Choice B: Ehlers-Danlos causes hyperflexible joints and skin, but not lens dislocation or thromboses.
   Choice C: PKU causes intellectual disability and fair skin with a musty odor, but not the skeletal or ocular features described here.
   Choice D: B6 deficiency can raise homocysteine and cause neuropathy, but by itself it wouldn’t produce the full picture of lens dislocation and Marfanoid features seen in homocystinuria.

10. A 4-day-old newborn is increasingly lethargic and refuses to feed. He vomits and has episodes of hypertonia and hypotonia. The physician notes a sweet “maple syrup” odor in the infant’s diaper. Labs show elevated branched-chain amino acids. Which enzyme defect is the most likely cause of this infant’s condition?
    A. Phenylalanine hydroxylase deficiency
    B. Ornithine transcarbamylase deficiency
    C. Propionyl-CoA carboxylase deficiency
    D. Cystathionine synthase deficiency
    E. Branched-chain α-ketoacid dehydrogenase deficiency

    Explanation: The correct answer is E. Maple syrup urine disease (MSUD) is caused by a defect in branched-chain α-ketoacid dehydrogenase, the enzyme complex needed to break down leucine, isoleucine, and valine. Affected infants present in the first days of life with poor feeding, vomiting, lethargy, dystonia, and urine that smells like maple syrup. If untreated, it leads to severe CNS damage. Treatment is dietary restriction of branched-chain amino acids and thiamine (B1) supplementation (a cofactor for the enzyme).
    Choice A: Phenylalanine hydroxylase deficiency (PKU) presents slightly later with musty odor and developmental delays, not the acute neonatal crisis with maple odor.
    Choice B: OTC deficiency (urea cycle disorder) causes hyperammonemia in neonates, but no maple syrup odor.
    Choice C: Propionyl-CoA carboxylase deficiency (propionic acidemia) causes severe metabolic acidosis in neonates, but not a maple syrup odor (and it involves a different step in amino acid breakdown).
    Choice D: Cystathionine synthase deficiency (homocystinuria) presents later in childhood with Marfanoid features and thrombosis, not an acute neonatal metabolic crisis.

11. A 3-day-old boy becomes lethargic and vomits frequently. He has tachypnea and poor feeding. Lab tests show a very high blood ammonia level. Urinalysis reveals elevated orotic acid. Which of the following is the most likely cause of this infant’s findings?
    A. Phenylketonuria
    B. Carbamoyl phosphate synthetase I deficiency
    C. Hereditary orotic aciduria (UMP synthase deficiency)
    D. N-acetylglutamate synthase deficiency
    E. Ornithine transcarbamylase deficiency

    Explanation: The correct answer is E. Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle disorder that causes hyperammonemia in neonates (especially boys). Excess carbamoyl phosphate is shunted to pyrimidine synthesis, leading to orotic acid in blood and urine. Key features: encephalopathy from ammonia (lethargy, vomiting, seizures) and no megaloblastic anemia (distinguishing it from hereditary orotic aciduria).
    Choice B: Carbamoyl phosphate synthetase I deficiency (AR) also causes neonatal hyperammonemia, but it would not cause orotic aciduria (because the block is before carbamoyl phosphate enters the pyrimidine pathway).
    Choice C: Hereditary orotic aciduria (UMP synthase defect) causes orotic acid buildup with megaloblastic anemia and growth failure, but no hyperammonemia (the infant would not have the severe neurologic signs from ammonia).
    Choice D: NAGS deficiency (required activator of CPS I) causes hyperammonemia like CPS I deficiency, without orotic aciduria (similar to option B).
    Choice A: PKU involves amino acid metabolism (phenylalanine) and causes a musty odor and developmental delay over time, not acute neonatal hyperammonemia with orotic acid.

12. A 3-year-old boy exhibits aggressive behavior and self-mutilation, biting his fingers and lips. He has developmental delay and dystonia. Exam shows orange crystals (gouty tophi) in his diaper area. Labs reveal hyperuricemia. Which enzyme deficiency is the most likely cause of this condition?
    A. Adenosine deaminase deficiency
    B. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency
    C. Phenylalanine hydroxylase deficiency
    D. Hexosaminidase A deficiency
    E. PRPP synthetase overactivity

    Explanation: The correct answer is B. This is Lesch-Nyhan syndrome, caused by a deficiency of HGPRT in the purine salvage pathway. In HGPRT deficiency, excess uric acid production leads to gout and kidney stones, and the lack of purine salvage causes self-injurious behavior, intellectual disability, and dystonia. It is an X-linked recessive disorder.
    Choice A: Adenosine deaminase deficiency causes SCID (severe combined immunodeficiency), not the neurological and behavioral findings here.
    Choice C: Phenylalanine hydroxylase deficiency (PKU) causes developmental delay and odor but not self-mutilation or gout.
    Choice D: Hexosaminidase A deficiency (Tay-Sachs) causes neurodegeneration and a cherry-red macula in infancy, without hyperuricemia or self-harm behavior.
    Choice E: PRPP synthetase overactivity can lead to gout by increasing purine synthesis, but it does not cause the neurological symptoms or self-mutilation seen in Lesch-Nyhan.

13. A 10-month-old girl has failure to thrive and a persistent anemia. She has developmental delays and is very pale. Labs reveal a macrocytic anemia with megaloblastic changes, but B12 and folate levels are normal. Urinalysis finds orotic acid crystals. Which of the following is the most likely diagnosis?
    A. Folate deficiency anemia
    B. Hereditary orotic aciduria
    C. Vitamin B12 deficiency anemia
    D. Ornithine transcarbamylase deficiency
    E. Iron deficiency anemia

    Explanation: The correct answer is B. Hereditary orotic aciduria is a rare AR disorder due to a defect in UMP synthase (orotate phosphoribosyltransferase/orotidine decarboxylase) in pyrimidine synthesis. It presents in infancy with megaloblastic anemia that does not improve with B12 or folate, along with failure to thrive and orotic acid crystalluria. There is no hyperammonemia (unlike OTC deficiency). Treatment is uridine supplementation to bypass the block.
    Choice A: Folate deficiency causes megaloblastic anemia, but it would improve with folate and is uncommon in a 10-month-old without risk factors.
    Choice C: B12 deficiency causes megaloblastic anemia (with neurologic symptoms) and elevated methylmalonic acid; normal B12 levels and lack of neuro signs make it unlikely.
    Choice D: OTC deficiency causes orotic aciduria with hyperammonemia in neonates, not an isolated megaloblastic anemia.
    Choice E: Iron deficiency causes microcytic anemia, not macrocytic.

14. A 9-month-old boy is found unresponsive in the morning. He had a minor illness the day before and ate poorly. In the ED, his blood glucose is 30 mg/dL, and no ketones are detected in blood or urine. He is resuscitated with IV glucose. Further tests show high levels of dicarboxylic acids in the urine. Which metabolic defect is the most likely cause of this episode?
    A. Von Gierke disease (glucose-6-phosphatase deficiency)
    B. Primary carnitine deficiency
    C. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
    D. Insulinoma
    E. Hers disease (hepatic glycogen phosphorylase deficiency)

    Explanation: The correct answer is C. MCAD deficiency is an AR disorder of fatty acid β-oxidation. Affected infants can’t oxidize medium-chain fatty acids, leading to severe hypoketotic hypoglycemia during fasting or illness, as seen here. They may accumulate dicarboxylic acids and can have seizures, liver dysfunction, or sudden death. Treatment is to avoid fasting and provide frequent carb-rich meals.
    Choice A: Von Gierke disease causes hypoglycemia but usually with lactic acidosis and ketosis can still occur via fat breakdown; plus it presents earlier with consistent issues, not sudden crisis after illness.
    Choice B: Primary carnitine deficiency also causes hypoketotic hypoglycemia and weakness/cardiomyopathy, but dicarboxylic aciduria strongly suggests an MCAD enzyme block.
    Choice D: Insulinoma (insulin-secreting tumor) causes hypoglycemia with low ketones, but it’s extremely rare in infants and not associated with dicarboxylic aciduria.
    Choice E: Hers disease (Type VI GSD) causes mild fasting hypoglycemia and hepatomegaly, not life-threatening episodes with no ketones; ketone production is not blocked in glycogen storage diseases.

15. A 25-year-old man suffers a myocardial infarction. He has very high LDL cholesterol. Exam shows yellow tendon xanthomas on his Achilles tendons. His father and grandfather had early heart attacks. Which lipid disorder is the most likely cause of his condition?
    A. Familial chylomicronemia (Type I hyperlipoproteinemia)
    B. Familial dysbetalipoproteinemia (Type III)
    C. Familial hypercholesterolemia (Type IIa)
    D. Abetalipoproteinemia
    E. Familial hypertriglyceridemia (Type IV)

    Explanation: The correct answer is C. Familial hypercholesterolemia (Type IIa) is an autosomal dominant disorder most often due to LDL receptor defects (or ApoB-100 mutations) that cause markedly elevated LDL levels. Patients develop tendon xanthomas (classically on the Achilles) and have a high risk of premature atherosclerosis (MIs in their 20s-30s).
    Choice A: Type I hyperlipoproteinemia (LPL or ApoC-II deficiency) causes extremely high triglycerides with pancreatitis and eruptive xanthomas, not high LDL or early MI.
    Choice B: Type III (ApoE defect) causes elevated chylomicron/VLDL remnants and palmar xanthomas, with premature atherosclerosis, but tendon xanthomas and such early MI strongly suggest Type IIa.
    Choice D: Abetalipoproteinemia causes an inability to form apo-B containing lipoproteins, leading to fat malabsorption and very low cholesterol; it does not cause high LDL or xanthomas.
    Choice E: Type IV hyperlipoproteinemia (VLDL overproduction) causes high triglycerides and pancreatitis risk; it isn’t characterized by tendon xanthomas or extremely high LDL.

16. A 9-month-old Ashkenazi Jewish infant is losing developmental milestones and motor skills. The baby is irritable and has feeding difficulty. Exam shows hypotonia, hepatosplenomegaly, and a “cherry-red” spot on the macula. Which of the following is the most likely diagnosis?
    A. Tay-Sachs disease
    B. Gaucher disease
    C. Metachromatic leukodystrophy
    D. Hurler syndrome
    E. Niemann-Pick disease

    Explanation: The correct answer is E. Niemann-Pick disease is caused by sphingomyelinase deficiency, leading to sphingomyelin accumulation. Infants (especially of Ashkenazi heritage) present with regression of skills, hypotonia, feeding difficulties, hepatosplenomegaly, and a cherry-red macula. Lipid-laden foam cells are seen. It is often fatal by early childhood.
    Choice A: Tay-Sachs (hexosaminidase A deficiency) also causes developmental regression and a cherry-red spot, but no hepatosplenomegaly (the abdomen is not enlarged in Tay-Sachs).
    Choice B: Gaucher (glucocerebrosidase deficiency) typically has hepatosplenomegaly and bone pain/crises, but usually no cherry-red spot and a later onset (childhood to adulthood).
    Choice C: Metachromatic leukodystrophy (arylsulfatase A deficiency) causes demyelination leading to ataxia and dementia in childhood, but not usually organomegaly or cherry-red spot.
    Choice D: Hurler syndrome (α-L-iduronidase deficiency) presents with coarse facial features, corneal clouding, hepatosplenomegaly, and developmental delay, but not a cherry-red macula.

17. A 30-year-old man experiences abdominal cramps, bloating, and diarrhea whenever he consumes milk. He can tolerate cheese or yogurt in moderation, but a glass of milk causes significant discomfort about an hour later. He has no weight loss or blood in stool. Which of the following is the most likely cause of his symptoms?
    A. Irritable bowel syndrome
    B. Celiac disease
    C. Giardiasis
    D. Pancreatic exocrine insufficiency
    E. Lactase deficiency

    Explanation: The correct answer is E. This classic presentation is lactose intolerance due to lactase deficiency. Lactase, a brush-border enzyme, normally breaks lactose into glucose and galactose. In many adults (especially of Asian, African, or Mediterranean descent), lactase levels decline (lactase nonpersistence), resulting in osmotic diarrhea, bloating, and cramping upon dairy intake. Undigested lactose is fermented by colonic bacteria, producing gas (hydrogen breath test is positive).
    Choice A: IBS can cause abdominal pain and bowel habit changes, but it is not specifically triggered by dairy and has a broader pattern of symptoms.
    Choice B: Celiac disease (gluten sensitivity) causes malabsorption, weight loss, possibly anemia, and can cause secondary lactose intolerance due to villous atrophy—but the primary trigger is gluten, not dairy.
    Choice C: Giardiasis (Giardia infection) can lead to temporary lactase deficiency after infection, but it usually involves a history of contaminated water and causes foul-smelling, greasy stools and weight loss.
    Choice D: Pancreatic insufficiency (e.g., chronic pancreatitis, CF) leads to malabsorption of fats and proteins, causing steatorrhea and weight loss, and is not primarily triggered by lactose intake.

18. The parents of a 5-year-old boy report he develops severe sunburns with blistering after minimal sun exposure. He has numerous freckle-like spots on sun-exposed skin and some scaly patches suspicious for early skin cancer. The physician suspects a defect in DNA repair. Which process is most likely impaired in this patient?
    A. Mismatch repair of DNA replication errors
    B. Base excision repair of deaminated bases
    C. Nonhomologous end joining of double-strand breaks
    D. Nucleotide excision repair of thymidine dimers
    E. Homologous recombination repair of double-strand breaks

    Explanation: The correct answer is D. This child’s extreme UV sensitivity and early skin lesions suggest xeroderma pigmentosum, an AR disorder due to defective nucleotide excision repair. UV light causes thymine-thymine dimers; normally, endonucleases recognize and remove these, allowing DNA Pol and ligase to repair. In XP, inability to fix pyrimidine dimers leads to cumulative DNA damage and skin cancers in childhood.
    Choice A: Defective mismatch repair causes Lynch syndrome (hereditary nonpolyposis colorectal cancer), not UV sensitivity.
    Choice B: Base excision repair fixes small base lesions (like spontaneous deamination) and is not associated with extreme photosensitivity.
    Choice C: Defective nonhomologous end joining (for double-strand breaks) is seen in disorders like ataxia-telangiectasia, which presents with ataxia, telangiectasias, and immune deficiency, not primarily sun sensitivity.
    Choice E: Homologous recombination repair defects occur in BRCA1/2 mutations (breast/ovarian cancer) and Fanconi anemia, which do not present with UV hypersensitivity.

19. A 28-year-old woman with a malar rash, photosensitivity, and arthritis has labs positive for anti–double-stranded DNA and anti-Smith antibodies (SLE). The Smith antigen is a protein that complexes with small nuclear RNA (snRNA) to form snRNPs. snRNPs are essential for which cellular process?
    A. Promoter recognition and initiation of transcription
    B. 5’ capping of mRNA
    C. 3’ polyadenylation of mRNA
    D. Splicing of pre-mRNA
    E. Translation initiation at the ribosome

    Explanation: The correct answer is D. Anti-Smith antibodies in SLE target snRNPs, which are critical components of the spliceosome. The spliceosome removes introns from pre-mRNA, precisely splicing together exons to form mature mRNA. Thus, snRNPs facilitate RNA splicing in the nucleus.
    Choice A: Promoter recognition is handled by general transcription factors and RNA polymerase II (TATA box binding, etc.), not by snRNPs.
    Choice B: 5’ capping is the addition of a 7-methylguanosine cap to the nascent mRNA, performed by capping enzymes early in transcription.
    Choice C: Polyadenylation is done by poly(A) polymerase following the polyadenylation signal, not by snRNPs.
    Choice E: Translation initiation involves initiation factors, the small ribosomal subunit, and initiator tRNA (not snRNPs, which work in RNA processing, not translation).

20. A 34-year-old man presents with severe abdominal pain, vomiting, and diarrhea 24 hours after eating wild mushrooms on a camping trip. He has elevated AST and ALT, indicating liver injury. The mushroom toxin α-amanitin primarily inhibits which of the following in hepatocytes?
    A. Eukaryotic RNA polymerase II
    B. Eukaryotic RNA polymerase I
    C. Eukaryotic RNA polymerase III
    D. Prokaryotic RNA polymerase
    E. Eukaryotic DNA polymerase δ

    Explanation: The correct answer is A. α-Amanitin from Amanita phalloides (death cap mushrooms) binds to and inhibits RNA polymerase II, which halts mRNA synthesis in eukaryotic cells. The liver is especially affected (rapidly dividing hepatocytes need active mRNA production), leading to fulminant hepatitis.
    Choice B: RNA Pol I makes rRNA in the nucleolus; not the primary target of α-amanitin.
    Choice C: RNA Pol III makes tRNA and 5S rRNA; relatively resistant to α-amanitin.
    Choice D: Prokaryotic RNA polymerase (DNA-dependent RNA pol) is inhibited by rifampin, not α-amanitin (which affects eukaryotes).
    Choice E: Eukaryotic DNA polymerase δ is involved in DNA replication, not transcription, and is not targeted by α-amanitin.

21. A 5-year-old boy who recently emigrated has fever, sore throat, and difficulty breathing. Exam shows a thick gray pharyngeal exudate and “bull neck” lymphadenopathy. He is not immunized. The bacterial exotoxin causing his illness acts by which mechanism?
    A. Cleaving host 60S ribosomal rRNA
    B. Activating adenylate cyclase via Gs ADP-ribosylation
    C. Disabling Gi proteins to increase cAMP
    D. Cleaving synaptobrevin to block neurotransmitter release
    E. ADP-ribosylation of eukaryotic elongation factor-2 (EF-2)

    Explanation: The correct answer is E. This is diphtheria, caused by Corynebacterium diphtheriae. Diphtheria toxin (and Pseudomonas exotoxin A) ADP-ribosylates and inactivates EF-2, halting protein synthesis in human cells, leading to cell death (necrosis in the throat pseudomembrane and heart/neural tissue damage).
    Choice A: Shiga toxin from Shigella (and Shiga-like toxin from EHEC) inactivates the 60S ribosomal subunit by removing an adenine from rRNA, not the mechanism of diphtheria toxin.
    Choice B: Cholera toxin (and E. coli LT) permanently activates Gs to increase cAMP, causing secretory diarrhea.
    Choice C: Pertussis toxin disables Gi, leading to increased cAMP and lymphocytosis in whooping cough.
    Choice D: Botulinum and tetanus toxins cleave SNARE proteins (like synaptobrevin) preventing neurotransmitter release, causing flaccid (botulinum) or spastic (tetanus) paralysis; diphtheria is a different mechanism.

22. A 50-year-old man with tuberculosis is started on streptomycin as part of therapy. Streptomycin’s mechanism of action primarily involves:
    A. Inhibition of peptidyl transferase on the 50S ribosomal subunit
    B. Blocking aminoacyl-tRNA binding to the A site on 30S
    C. Premature chain termination by acting as a tRNA analog
    D. Blocking translocation from A site to P site on 50S
    E. Binding the 30S ribosomal subunit and causing mRNA misreading

    Explanation: The correct answer is E. Streptomycin is an aminoglycoside that binds the 30S ribosomal subunit in prokaryotes, interfering with the initiation complex and causing misreading of mRNA. This leads to defective bacterial proteins and inhibition of protein synthesis (bactericidal effect).
    Choice A: Inhibition of peptidyl transferase on the 50S is the mechanism of chloramphenicol.
    Choice B: Blocking tRNA binding to the A site (30S) is how tetracyclines work.
    Choice C: Premature chain termination by tRNA mimicry is the action of the antibiotic puromycin (not used clinically for infections).
    Choice D: Blocking translocation on the 50S is the mechanism of macrolides and clindamycin.

23. A 4-year-old boy with developmental delay and obesity has insatiable appetite and sneaks food. He has hypotonia, short stature, and small testes. Genetic testing shows a deletion on chromosome 15. Which genetic mechanism is most likely responsible?
    A. Deletion of paternal 15q with maternal imprinting of that region
    B. Deletion of maternal 15q with paternal imprinting of that region
    C. CGG trinucleotide repeat expansion on the X chromosome
    D. Mitochondrial DNA mutation (maternal inheritance)
    E. Random X-inactivation (Lyonization)

    Explanation: The correct answer is A. This is Prader-Willi syndrome, most often due to a microdeletion of the paternal chromosome 15q11-q13 with imprinting (silencing) of the maternal allele in that region. The result is loss of paternal gene function in that area. It presents with hyperphagia, obesity, hypotonia, intellectual disability, and hypogonadism. (Less commonly, maternal uniparental disomy of 15 can cause it.)
    Choice B: A maternal 15q deletion with paternal imprinting describes Angelman syndrome (inappropriate laughter, seizures, ataxia, severe intellectual disability due to loss of the maternal UBE3A gene).
    Choice C: CGG repeat on X is Fragile X syndrome (intellectual disability, large ears/jaw, macroorchidism), not this presentation.
    Choice D: Mitochondrial DNA mutations (like MELAS, Leber optic neuropathy) are maternally inherited and cause neuromuscular symptoms, not this syndrome’s features.
    Choice E: Random X-inactivation occurs in all females (normal lyonization), not related to this father-to-son transmitted deletion syndrome.

24. A researcher wants to see if a certain oncogene is overexpressed (at the mRNA level) in tumor cells versus normal cells. Which technique would be most appropriate to compare mRNA levels of this gene?
    A. Northern blot
    B. Southern blot
    C. Western blot
    D. ELISA
    E. PCR (without reverse transcription)

    Explanation: The correct answer is A. A Northern blot detects specific RNA molecules. The researcher would isolate RNA from tumor and normal cells, run on a gel, transfer to a membrane, and probe for the oncogene mRNA. The band intensity reflects mRNA abundance, revealing overexpression if present.
    Choice B: Southern blot detects DNA sequences, not mRNA expression.
    Choice C: Western blot detects proteins using antibodies, which measures protein, not mRNA.
    Choice D: ELISA detects proteins or small molecules (antigens/antibodies) in solution, not mRNA.
    Choice E: Standard PCR amplifies DNA. To measure mRNA, one would need RT-PCR (reverse transcriptase PCR) to convert mRNA to cDNA first; a Northern blot is a direct method for RNA comparison.

25. Cultured cancer cells activate telomerase, allowing indefinite division without telomere shortening. Telomerase has which enzymatic activity?
    A. DNA-dependent DNA polymerase
    B. DNA-dependent RNA polymerase
    C. RNA-dependent RNA polymerase
    D. RNA-dependent DNA polymerase
    E. RNA polymerase with 3'→5' exonuclease activity

    Explanation: The correct answer is D. Telomerase is an RNA-dependent DNA polymerase, i.e., a reverse transcriptase. It carries its own RNA template and adds DNA repeats (TTAGGG) to chromosome ends (telomeres), preventing their shortening in each cell division. This is how stem cells and cancer cells maintain telomere length.
    Choice A: DNA-dependent DNA polymerases are normal DNA polymerases that replicate DNA from a DNA template (not telomerase).
    Choice B: DNA-dependent RNA polymerases are the RNA polymerases that transcribe DNA into RNA (e.g., RNA Pol II for mRNA).
    Choice C: RNA-dependent RNA polymerases copy RNA from an RNA template (found in RNA viruses, not human cells).
    Choice E: RNA polymerases do not have 3'→5' exonuclease proofreading and this is not related to telomerase.

26. A 4-year-old boy has difficulty rising from the floor, using his hands to push off his legs (Gowers sign). He began walking late and now has calf pseudohypertrophy. His uncle had similar symptoms and was wheelchair-bound as a teen. A mutation in the dystrophin gene is suspected. What type of mutation most likely caused this patient’s condition?
    A. Missense mutation
    B. Nonsense mutation
    C. Splice site mutation
    D. Frameshift mutation
    E. Trinucleotide repeat expansion

    Explanation: The correct answer is D. Duchenne muscular dystrophy (DMD) is usually due to frameshift mutations (deletions/insertions not in multiples of 3) in the dystrophin gene, leading to a premature stop codon and nonfunctional truncated protein. This causes early childhood onset of progressive muscle weakness, Gowers sign, and pseudohypertrophy of calves (replacement of muscle with fat).
    Choice A: Missense mutations (single amino acid substitutions) in dystrophin tend to cause the milder Becker muscular dystrophy, not classic Duchenne.
    Choice B: Nonsense mutations (early stop codon) could cause DMD if they occur, but the most common cause is frameshift deletion.
    Choice C: Splice site mutations can cause many diseases but are not the classic cause of Duchenne (though they can occur in some cases).
    Choice E: Trinucleotide repeats cause diseases like myotonic dystrophy, Huntington, fragile X, etc., not DMD.

27. A 6-month-old African American boy has swollen, painful hands and feet (dactylitis). Hemoglobin electrophoresis confirms sickle cell anemia. His disease is caused by which mutation in the β-globin gene?
    A. Frameshift mutation
    B. Nonsense (stop) mutation
    C. Silent (synonymous) mutation
    D. Missense (amino acid substitution) mutation
    E. Trinucleotide repeat expansion

    Explanation: The correct answer is D. Sickle cell anemia is caused by a missense point mutation in the β-globin gene. Specifically, an A to T substitution in the DNA leads to a glutamic acid → valine substitution at position 6 of β-globin. This single amino acid change produces HbS, which polymerizes under low oxygen, causing RBC sickling and vaso-occlusive episodes (like dactylitis in infants).
    Choice A: Frameshift mutations (due to base insertions/deletions) would drastically alter the protein and typically produce a nonfunctional protein, not the case in sickle cell where hemoglobin is produced but abnormal.
    Choice B: Nonsense mutation would result in a truncated β-globin; sickle cell has a full-length β-globin.
    Choice C: Silent mutation does not change the amino acid and is clinically silent.
    Choice E: Trinucleotide repeat expansions cause other disorders (e.g., Huntington disease, fragile X), not sickle cell.

28. A 7-year-old boy has progressive difficulty with balance and recurrent sinus and lung infections. He has spider angiomas on his sclerae and skin. Labs show IgA deficiency. What cellular process is most likely defective in this patient?
    A. DNA mismatch repair
    B. Nucleotide excision repair
    C. V(D)J recombination
    D. 3'→5' DNA exonuclease proofreading
    E. DNA double-strand break repair (nonhomologous end joining)

    Explanation: The correct answer is E. This is ataxia-telangiectasia, caused by mutations in the ATM gene, leading to defective DNA double-strand break repair (via nonhomologous end joining). The classic triad is cerebellar ataxia, oculocutaneous telangiectasias, and immunodeficiency (especially IgA). Patients are also sensitive to ionizing radiation (due to the DNA repair defect).
    Choice A: Mismatch repair defects cause Lynch syndrome (colon cancer predisposition), not this immunoneurologic syndrome.
    Choice B: Nucleotide excision repair defects cause xeroderma pigmentosum (UV sensitivity, skin cancers).
    Choice C: V(D)J recombination defects (as in severe combined immunodeficiencies) cause immune failure but not the telangiectasia or ataxia.
    Choice D: Proofreading exonuclease issues could cause increased mutations but are not linked to a specific syndrome like this.

29. Multiple members of a family develop colon cancer at young ages, often in the right colon, with few or no polyps. Several also had endometrial cancer. This picture is suggestive of Lynch syndrome (HNPCC). Which is the most likely underlying cause?
    A. Germline APC gene mutation
    B. Inherited TP53 mutation (Li-Fraumeni syndrome)
    C. Defective nucleotide excision repair enzymes
    D. Inherited mutation in a DNA mismatch repair gene
    E. Germline RB1 tumor suppressor mutation

    Explanation: The correct answer is D. Lynch syndrome (HNPCC) results from an inherited mutation in a DNA mismatch repair gene (e.g., MSH2, MLH1) leading to microsatellite instability. It predisposes mainly to colon cancer (especially right-sided, with few polyps) and endometrial cancer, among others. Autosomal dominant inheritance.
    Choice A: Germline APC mutation causes familial adenomatous polyposis (thousands of polyps, colon cancer), a different syndrome.
    Choice B: TP53 mutation is Li-Fraumeni, with diverse early tumors (sarcoma, breast, leukemia, etc.), not specifically colon/endometrial cancer.
    Choice C: Nucleotide excision repair defects cause xeroderma pigmentosum, not colon cancer syndromes.
    Choice E: RB1 mutation causes familial retinoblastoma (eye tumors in childhood, osteosarcoma risk), not this pattern.

30. A 45-year-old man with TB is on RIPE therapy (rifampin, isoniazid, pyrazinamide, ethambutol). He is counseled that one drug may cause orange-red body fluids. Rifampin’s mechanism of action is:
    A. Inhibition of mycobacterial mycolic acid synthesis
    B. Inhibition of arabinosyl transferase (arabinogalactan synthesis)
    C. Acidification of phagolysosomes to kill mycobacteria
    D. Inhibition of DNA-dependent RNA polymerase in bacteria
    E. Inhibition of bacterial DNA gyrase (topoisomerase II)

    Explanation: The correct answer is D. Rifampin binds the β-subunit of the bacterial DNA-dependent RNA polymerase, inhibiting transcription in Mycobacterium tuberculosis (and other bacteria). It is a key TB drug and causes harmless orange discoloration of secretions (tears, urine).
    Choice A: Inhibition of mycolic acid synthesis is isoniazid’s mechanism.
    Choice B: Inhibition of arabinogalactan synthesis is ethambutol’s mechanism.
    Choice C: Pyrazinamide works best in acidic phagolysosomes and disrupts mycobacterial membranes/energy, but rifampin’s effect is on RNA polymerase.
    Choice E: Inhibition of DNA gyrase is the mechanism of fluoroquinolones, not rifampin.

31. In a lab experiment, an enzyme-catalyzed reaction proceeds millions of times faster with the enzyme than without. Which of the following explains how enzymes speed up reactions?
    A. Making the overall ΔG more negative
    B. Shifting the reaction equilibrium toward products
    C. Lowering the activation energy
    D. Altering the equilibrium constant (K_eq)
    E. Being consumed to provide energy for the reaction

    Explanation: The correct answer is C. Enzymes accelerate reactions by lowering the activation energy (Eₐ) needed to reach the transition state. By stabilizing the transition state, they increase reaction rate. Enzymes do not change ΔG, equilibrium position, or K_eq; they are also not consumed in the reaction.
    Choice A: Enzymes don’t change the reaction’s free energy change (ΔG). They can catalyze favorable or unfavorable reactions (the latter often coupled to ATP hydrolysis).
    Choice B/D: Enzymes do not shift equilibrium or change K_eq; they help the system reach equilibrium faster, but the ratio of products to reactants at equilibrium is unchanged.
    Choice E: Enzymes are not used up in reactions; they emerge unchanged.

32. A patient with methanol poisoning is treated with ethanol, which competitively inhibits alcohol dehydrogenase. What are the kinetic effects of a competitive inhibitor on an enzyme?
    A. Vmax unchanged; Km increased
    B. Vmax unchanged; Km decreased
    C. Vmax decreased; Km increased
    D. Vmax decreased; Km unchanged
    E. Vmax decreased; Km decreased

    Explanation: The correct answer is A. A competitive inhibitor increases the apparent Km (more substrate is needed to reach half-max velocity, reflecting reduced apparent affinity) but does not change Vmax (because at high substrate concentrations, the inhibitor can be outcompeted and the same maximal velocity can be achieved). In the case of methanol poisoning, ethanol competes for alcohol dehydrogenase, slowing methanol metabolism without reducing the enzyme’s ultimate capacity when substrate is high.
    Choices B/C/D/E: Among these, only A describes classic competitive inhibition. For reference, noncompetitive inhibitors decrease Vmax (less enzyme available to work) but do not change Km (affinity for substrate of remaining enzyme is unchanged).

33. Low-dose aspirin irreversibly inhibits platelet cyclooxygenase (COX-1), preventing thromboxane A₂ formation and reducing clotting. Platelet function is affected for ~7–10 days (platelet lifespan) after aspirin. Which best describes aspirin’s mechanism in this context?
    A. Reversible noncompetitive inhibition of COX
    B. Reversible competitive inhibition of COX
    C. Allosteric inhibition of thrombin
    D. Irreversible acetylation of COX active site
    E. Irreversible blockade of platelet ADP receptors

    Explanation: The correct answer is D. Aspirin irreversibly acetylates a serine in the active site of COX-1 (and COX-2), permanently inactivating the enzyme in platelets. Since platelets have no nucleus, they cannot make new enzyme; they regain COX function only when new platelets are made. This irreversibly stops thromboxane A₂ production for the platelet’s lifespan.
    Choice A: Aspirin’s inhibition is irreversible, not reversible, and it is at the active site (competitive) rather than noncompetitive.
    Choice B: It’s not reversible; other NSAIDs (ibuprofen) are reversible competitive inhibitors of COX.
    Choice C: Aspirin does not inhibit thrombin; it works on cyclooxygenase.
    Choice E: Irreversible ADP receptor blockers (like clopidogrel) are a different class of antiplatelet drugs, not aspirin’s mechanism.

34. A 55-year-old man with high cholesterol is prescribed atorvastatin. Statins lower cholesterol by inhibiting which enzyme?
    A. Hormone-sensitive lipase
    B. HMG-CoA reductase
    C. HMG-CoA lyase
    D. LCAT (lecithin-cholesterol acyltransferase)
    E. CETP (cholesteryl ester transfer protein)

    Explanation: The correct answer is B. Statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in hepatic cholesterol synthesis, thereby reducing cholesterol production. This causes hepatocytes to upregulate LDL receptors and remove more LDL from blood.
    Choice A: Hormone-sensitive lipase mobilizes fat from adipose tissue; not targeted by statins.
    Choice C: HMG-CoA lyase is in the ketogenesis pathway (converts HMG-CoA to acetoacetate), unrelated to statins.
    Choice D: LCAT esterifies cholesterol in HDL; not the mechanism of statins.
    Choice E: CETP transfers cholesteryl esters between lipoproteins; again, not how statins work.

35. High insulin increases fructose 2,6-bisphosphate in hepatocytes. Fructose 2,6-bisphosphate allosterically favors which pathway?
    A. Gluconeogenesis by activating fructose-1,6-bisphosphatase
    B. Gluconeogenesis by inducing PEP carboxykinase
    C. Glycolysis by activating phosphofructokinase-1
    D. Glycolysis by inducing hexokinase
    E. Ketogenesis by activating HMG-CoA synthase

    Explanation: The correct answer is C. Fructose 2,6-bisphosphate is a potent activator of phosphofructokinase-1 (PFK-1), the rate-limiting enzyme of glycolysis, thereby increasing glycolysis. Concurrently, F2,6-BP inhibits fructose-1,6-bisphosphatase, thus suppressing gluconeogenesis. This shift happens in the fed state (high insulin) to promote glucose utilization/storage.
    Choice A/B: F2,6-BP inhibits gluconeogenesis (it inhibits F1,6-bisphosphatase and would downregulate PEPCK expression under insulin).
    Choice D: Hexokinase is not the key regulated step in liver (glucokinase is, but F2,6-BP acts at PFK-1 step).
    Choice E: Ketogenesis is active in fasting (low insulin); F2,6-BP does not activate ketogenesis.

36. A 20-year-old woman has mild fasting hyperglycemia (~115 mg/dL) on routine tests. She is fit and not obese. Her father and grandfather had similar “mild diabetes” controlled with diet (MODY). Which enzyme mutation in pancreatic β-cells is most likely the cause?
    A. Hexokinase
    B. Glucokinase
    C. Glycogen synthase
    D. Glucose-6-phosphatase
    E. GLUT4 transporter

    Explanation: The correct answer is B. This describes MODY2, caused by a heterozygous mutation in glucokinase in pancreatic β-cells. Glucokinase (a glucose sensor with a higher Km) mutations raise the threshold for insulin release, causing mild, stable hyperglycemia. It’s often detected incidentally or during pregnancy and is managed with diet.
    Choice A: Hexokinase is in most tissues; MODY from hexokinase is not known.
    Choice C: Glycogen synthase mutations would affect glycogen storage rather than cause isolated mild hyperglycemia in a dominant pattern.
    Choice D: Glucose-6-phosphatase mutations cause Von Gierke disease (severe hypoglycemia, not hyperglycemia).
    Choice E: GLUT4 is an insulin-responsive transporter in muscle/fat; no known MODY from GLUT4, and a defect would cause insulin resistance and higher blood sugars.

37. Hemoglobin’s O₂ binding curve is sigmoidal, whereas myoglobin’s is hyperbolic. Why is hemoglobin’s curve sigmoidal?
    A. Hemoglobin follows Michaelis-Menten kinetics
    B. Hemoglobin is monomeric like myoglobin
    C. Hemoglobin’s O₂ affinity decreases as more O₂ binds
    D. Hemoglobin is not affected by allosteric regulators
    E. Hemoglobin exhibits cooperative binding of O₂ between subunits

    Explanation: The correct answer is E. Hemoglobin’s tetrameric structure leads to cooperative binding: binding of one O₂ increases the affinity of remaining subunits (positive cooperativity), producing a sigmoidal O₂ dissociation curve. This allows efficient O₂ loading in lungs and unloading in tissues. Myoglobin, a monomer, has no cooperativity, yielding a hyperbolic curve.
    Choice A: Michaelis-Menten describes enzyme kinetics, not directly relevant to O₂ binding curves.
    Choice B: Hemoglobin is tetrameric, not monomeric.
    Choice C: Hemoglobin’s affinity increases as each O₂ binds (until fully saturated); it decreases when O₂ unloads (facilitating further unloading).
    Choice D: Hemoglobin is affected by allosteric regulators (H⁺, CO₂, 2,3-BPG, temperature), which shift its curve; myoglobin isn’t.

38. A farmer accidentally ingests insecticide containing arsenic. He develops vomiting, rice-water diarrhea, hypotension, and garlic odor on breath. Arsenic inhibits lipoic acid, a cofactor for which enzyme complex?
    A. Pyruvate dehydrogenase
    B. Aconitase (TCA cycle)
    C. Cytochrome c oxidase (ETC)
    D. Phosphofructokinase-1 (glycolysis)
    E. Glucose-6-phosphate dehydrogenase (HMP shunt)

    Explanation: The correct answer is A. Arsenic poisoning inhibits lipoic acid, a cofactor for the pyruvate dehydrogenase complex (and α-ketoglutarate dehydrogenase, BCKD). Inhibiting PDH leads to buildup of pyruvate and lactic acidosis. Clinical signs include GI distress, hypotension, and a garlic odor on breath.
    Choice B: Aconitase is in TCA (inhibited by fluoroacetate, not arsenic).
    Choice C: Cytochrome c oxidase is Complex IV in ETC (inhibited by cyanide/CO).
    Choice D: PFK-1 is glycolysis’s rate-limiter (regulated by F2,6-BP, not arsenic).
    Choice E: G6PD is in the HMP shunt (causes hemolysis when deficient, not directly affected by arsenic).

39. A 5-year-old boy in a developing country has night blindness and frequent respiratory infections. Exam shows Bitot spots (foamy keratin debris) on conjunctiva and dry scaly skin. These findings suggest a deficiency of:
    A. Vitamin A
    B. Vitamin B1
    C. Vitamin C
    D. Vitamin D
    E. Vitamin K

    Explanation: The correct answer is A. Vitamin A (retinol) deficiency causes night blindness, xerosis (dry conjunctiva and skin), Bitot spots, and vulnerability to infections (especially measles). Vitamin A is crucial for vision (component of retinal pigments) and maintaining epithelial tissues.
    Choice B (B1) causes beriberi or Wernicke-Korsakoff, not night blindness.
    Choice C (C) causes scurvy (bleeding gums, poor healing).
    Choice D (D) causes rickets/osteomalacia (bone problems).
    Choice E (K) causes bleeding diathesis (coagulopathy).

40. A 16-year-old girl took high-dose vitamin supplements for months to improve her skin. She now has headaches, joint pain, and peeling skin. Exam shows papilledema (increased intracranial pressure). Which vitamin in excess is the likely cause?
    A. Vitamin D
    B. Vitamin E
    C. Vitamin A
    D. Vitamin B6
    E. Vitamin C

    Explanation: The correct answer is C. Hypervitaminosis A (vitamin A toxicity) can cause pseudotumor cerebri (increased intracranial pressure with headaches, papilledema), dry skin (desquamation), liver damage, and bone/joint pains. Chronic vitamin A overdose (or use of isotretinoin) is also teratogenic.
    Choice A: Excess D causes hypercalcemia (stones, bones, groans) but not intracranial hypertension or skin peeling.
    Choice B: Excess E can cause hemorrhagic stroke risk and necrotizing enterocolitis in infants, not these symptoms.
    Choice D: Excess B6 can cause peripheral neuropathy.
    Choice E: Excess C can cause GI upset, kidney stones, and iron overload, but not pseudotumor cerebri.

41. A 58-year-old alcoholic man is confused and ataxic with nystagmus. He confabulates to fill memory gaps. This neurologic syndrome is most commonly associated with deficiency of:
    A. Vitamin B3 (niacin)
    B. Vitamin B6 (pyridoxine)
    C. Vitamin B9 (folate)
    D. Vitamin B12 (cobalamin)
    E. Vitamin B1 (thiamine)

    Explanation: The correct answer is E. This is Wernicke-Korsakoff syndrome (encephalopathy + confabulation/amnesia), associated with thiamine (B1) deficiency in chronic alcoholics. Thiamine is a cofactor for pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase; its deficiency impairs glucose metabolism in the brain. Treatment requires IV thiamine (before glucose).
    Choice A: Niacin (B3) deficiency causes pellagra (dermatitis, diarrhea, dementia).
    Choice B: Pyridoxine (B6) deficiency causes peripheral neuropathy and sideroblastic anemia, not this syndrome.
    Choice C: Folate (B9) deficiency causes megaloblastic anemia (and risk of neural tube defects in fetus).
    Choice D: Cobalamin (B12) deficiency causes megaloblastic anemia and neuropathy (subacute combined degeneration), but Wernicke-Korsakoff in alcoholics is classically B1.

42. A 34-year-old malnourished man from a refugee camp has diarrhea, dermatitis, and dementia. His skin has a bilateral rash in sun-exposed areas. His diet is mostly corn. Which vitamin deficiency is the most likely cause?
    A. Vitamin B2 (riboflavin)
    B. Vitamin B6 (pyridoxine)
    C. Vitamin B3 (niacin)
    D. Vitamin B1 (thiamine)
    E. Vitamin C (ascorbic acid)

    Explanation: The correct answer is C. Niacin (vitamin B3) deficiency causes pellagra, classically with the “3 D’s”: dermatitis (photosensitive rash), diarrhea, and dementia. It often occurs in diets reliant on corn (low in tryptophan, a niacin precursor) or due to conditions like Hartnup disease (impaired tryptophan absorption) or carcinoid syndrome (tryptophan used to make serotonin).
    Choice A: Riboflavin (B2) deficiency causes cheilosis and corneal vascularization.
    Choice B: Pyridoxine (B6) deficiency causes neuropathy and sideroblastic anemia (and can cause cheilosis/glossitis, but not the full pellagra picture).
    Choice D: Thiamine (B1) deficiency causes beriberi or Wernicke-Korsakoff.
    Choice E: Vitamin C deficiency causes scurvy (bleeding gums, etc.).

43. A 30-year-old man treated for TB develops tingling in his feet and a microcytic anemia with ringed sideroblasts. His symptoms improve with pyridoxine supplementation. Which vitamin was deficient?
    A. Vitamin B2 (riboflavin)
    B. Vitamin B6 (pyridoxine)
    C. Vitamin B12 (cobalamin)
    D. Vitamin E
    E. Vitamin K

    Explanation: The correct answer is B. Vitamin B6 (pyridoxine) deficiency, often caused by isoniazid therapy, leads to peripheral neuropathy and sideroblastic anemia. Pyridoxine is a cofactor for δ-ALA synthase in heme synthesis (among many other reactions); without it, iron cannot be incorporated into heme, forming ringed sideroblasts. Supplementation prevents these side effects.
    Choice A: B2 deficiency causes mouth sores and corneal changes, not this picture.
    Choice C: B12 deficiency causes macrocytic anemia and neurologic issues (dorsal column damage), not sideroblasts.
    Choice D: Vitamin E deficiency can cause neuropathy and hemolytic anemia, but here the key is sideroblasts and TB treatment (isoniazid), pointing to B6.
    Choice E: Vitamin K deficiency causes bleeding (coagulopathy).

44. A bodybuilder drinks raw egg whites daily. He develops a rash, hair loss, and muscle pains. Lab shows mild lactic acidosis. Excess raw egg white consumption causes deficiency of which vitamin?
    A. Vitamin B1
    B. Vitamin B3
    C. Vitamin B5
    D. Vitamin B9
    E. Vitamin B7

    Explanation: The correct answer is E. Raw egg whites contain avidin, which binds biotin (B7) and prevents its absorption. Biotin is a cofactor for carboxylation enzymes (pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase). Deficiency causes dermatitis, alopecia, and enteritis, and can lead to metabolic acidosis (e.g., lactic acidosis from pyruvate carboxylase impairment).
    Choices A, B, C, D: Thiamine, niacin, pantothenic acid, and folate deficiencies have different manifestations (beriberi/Wernicke-Korsakoff; pellagra; paresthesias/adrenal problems; megaloblastic anemia, respectively) and are not classically linked to raw egg consumption.

45. A 28-year-old alcoholic woman has fatigue and pallor. Labs show macrocytic anemia (MCV 110) with hypersegmented neutrophils. Methylmalonic acid level is normal. Which vitamin is most likely deficient?
    A. Folate (B9)
    B. Niacin (B3)
    C. Riboflavin (B2)
    D. Cobalamin (B12)
    E. Ascorbic acid (C)

    Explanation: The correct answer is A. Folate (B9) deficiency causes megaloblastic anemia with macro-ovalocytes and hypersegmented neutrophils. It’s common in alcoholics and pregnancy due to poor intake or increased need. Normal methylmalonic acid and absence of neurologic symptoms point to folate (B12 deficiency causes high MMA and neuro issues).
    Choice B: Niacin deficiency causes pellagra, not isolated anemia.
    Choice C: Riboflavin deficiency causes cheilosis and corneal vascularization.
    Choice D: B12 deficiency also causes macrocytic anemia but typically with neurologic symptoms and elevated MMA.
    Choice E: Vitamin C deficiency (scurvy) causes gum bleeding, not macrocytosis.

46. A 72-year-old woman has tingling in her feet, difficulty walking, and fatigue. Exam: loss of position/vibration sense in feet (positive Romberg). Labs: macrocytic anemia. Which vitamin is deficient?
    A. Thiamine (B1)
    B. Folate (B9)
    C. Cobalamin (B12)
    D. Vitamin E
    E. Vitamin B6

    Explanation: The correct answer is C. Vitamin B12 (cobalamin) deficiency causes megaloblastic anemia and neurologic symptoms (posterior column degeneration → loss of proprioception/vibration, gait instability; and lateral CST → spasticity if advanced). In older adults, pernicious anemia (autoimmune loss of intrinsic factor) is a common cause.
    Choice A: Thiamine deficiency causes Wernicke-Korsakoff or beriberi, not combined anemia and dorsal column signs.
    Choice B: Folate deficiency causes macrocytic anemia but no neurologic deficits.
    Choice D: Vitamin E deficiency can cause posterior column symptoms and hemolysis, but it doesn’t cause macrocytosis.
    Choice E: B6 deficiency causes neuropathy and sideroblastic anemia, not this presentation.

47. A 65-year-old widower with a “tea and toast” diet has fatigue and bleeding gums. He has multiple bruises and poor wound healing. These findings are most likely due to a deficiency of:
    A. Vitamin A
    B. Vitamin C
    C. Vitamin K
    D. Thiamine (B1)
    E. Vitamin D

    Explanation: The correct answer is B. This is scurvy from vitamin C (ascorbic acid) deficiency. Vitamin C is required for hydroxylation of proline and lysine in collagen. Lack of vitamin C leads to defective collagen → gum bleeding, easy bruising, perifollicular hemorrhages, and poor wound healing. It may occur in the elderly or alcoholics with poor diets.
    Choice A: Vitamin A deficiency causes night blindness and xerosis, not scurvy symptoms.
    Choice C: Vitamin K deficiency causes bleeding due to low clotting factors, but typically internal bleeding (e.g., hematomas) rather than collagen-related gum bleeding and skin findings.
    Choice D: Thiamine deficiency causes neurologic/cardiac issues (beriberi, Wernicke-Korsakoff).
    Choice E: Vitamin D deficiency causes bone demineralization (rickets/osteomalacia), not bleeding.

48. A 1-year-old boy (dark-skinned) is exclusively breastfed and kept mostly indoors. He has delayed motor development and bowing of the legs once he started walking. He also has widening of the wrists and costochondral beading (rachitic rosary). What vitamin deficiency is the cause?
    A. Vitamin A
    B. Vitamin D
    C. Vitamin K
    D. Folate
    E. Niacin

    Explanation: The correct answer is B. This child has rickets due to vitamin D deficiency. Dark skin (more melanin) and exclusive breastfeeding without supplementation increase risk, especially with limited sun. Vitamin D is needed for calcium and phosphate absorption; deficiency leads to poor bone mineralization (bowed legs, rachitic rosary, frontal bossing).
    Choices A, C, D, E: None of these cause rickets. (A affects vision/skin, C causes bleeding, D [folate] causes anemia, E [niacin] causes pellagra.)

49. A 3-day-old newborn, born at home without interventions, has bleeding from the umbilical stump and cephalohematoma. The baby hasn’t received any injections. What vitamin deficiency is likely?
    A. Vitamin C
    B. Vitamin D
    C. Vitamin K
    D. Folate (B9)
    E. Cobalamin (B12)

    Explanation: The correct answer is C. This is classic for hemorrhagic disease of the newborn due to vitamin K deficiency. Newborns lack gut bacteria to synthesize vitamin K, and breast milk has low vitamin K. Without prophylactic vitamin K shot at birth, infants can have serious bleeding (umbilical, intracranial). Vitamin K is required for activation of clotting factors II, VII, IX, X.
    Choice A: Vitamin C deficiency (scurvy) wouldn’t present at 3 days old.
    Choice B: Vitamin D deficiency causes rickets over time, not acute bleeding.
    Choice D/E: Folate or B12 deficiency in a newborn would present with anemia later, not acute bleeding (and maternal stores usually suffice initially unless mother was deficient).

50. A 19-year-old man with cystic fibrosis has worsening ataxia and loss of vibration sense in his legs. He also has hemolytic anemia. These findings in the context of fat malabsorption are most likely due to deficiency of:
    A. Vitamin A
    B. Vitamin D
    C. Vitamin E
    D. Vitamin K
    E. Thiamine (B1)

    Explanation: The correct answer is C. Vitamin E deficiency (fat-soluble, malabsorbed in CF) causes neurological dysfunction (dorsal column and spinocerebellar tract degeneration, similar to B12 deficiency but without megaloblastic anemia) and hemolytic anemia (due to poor antioxidant protection of RBC membranes).
    Choice A: Vitamin A deficiency causes night blindness and squamous metaplasia, not these neurologic or hematologic issues.
    Choice B: Vitamin D deficiency causes bone problems (osteomalacia).
    Choice D: Vitamin K deficiency causes bleeding, not neuro problems or hemolysis.
    Choice E: Thiamine deficiency (B1) causes Wernicke-Korsakoff or beriberi, with different neurologic findings and no hemolysis.

51. A 3-year-old child in a famine has edema, ascites, an enlarged fatty liver, muscle wasting, and depigmented hair with flaky skin lesions. His diet is almost all cornmeal with very little protein. What is the most likely diagnosis?
    A. Marasmus (total calorie malnutrition)
    B. Kwashiorkor (protein malnutrition)
    C. Cachexia due to chronic disease
    D. Vitamin B12 deficiency
    E. Scurvy (vitamin C deficiency)

    Explanation: The correct answer is B. This child has Kwashiorkor, due to protein malnutrition (with adequate calories). Kwashiorkor is characterized by edema (low plasma albumin → swollen belly, legs), fatty liver (impaired apolipoprotein synthesis → fat accumulates in liver), anemia, skin lesions (“flaky paint” dermatitis), and hair changes. Think MEAL: Malnutrition, Edema, Anemia, Liver (fatty).
    Choice A: Marasmus is total calorie malnutrition leading to severe wasting but no edema or fatty liver (the child is just very skinny).
    Choice C: Cachexia is wasting due to chronic illness (cancer, AIDS); here it’s dietary.
    Choice D: B12 deficiency in a 3-year-old is unlikely, and would cause anemia and neuro issues, not the edema and fatty liver.
    Choice E: Scurvy causes gum bleeding and poor wound healing, not the features here.

52. A 14-year-old boy has delayed puberty and anosmia (can’t smell). He also has poor wound healing and a scaly, pustular rash around his mouth and on his extremities. His diet is very limited. These findings are most suggestive of a deficiency in:
    A. Iodine
    B. Copper
    C. Selenium
    D. Chromium
    E. Zinc

    Explanation: The correct answer is E. Zinc deficiency causes delayed wound healing, hypogonadism (delayed sexual maturation), decreased adult hair (axillary, facial, pubic), anosmia, and dermatitis (especially around orifices—perioral rash, acral dermatitis). Zinc is needed for many enzymes and transcription factor structures (zinc fingers). It can occur with malnutrition or malabsorption, or in genetic zinc uptake disorders (acrodermatitis enteropathica).
    Choice A: Iodine deficiency causes goiter and hypothyroidism (cretinism in children).
    Choice B: Copper deficiency (e.g., Menkes disease) causes brittle “kinky” hair, neuro problems, and anemia, not exactly this picture.
    Choice C: Selenium deficiency can cause cardiomyopathy (Keshan disease) and hypothyroid features.
    Choice D: Chromium deficiency can impair glucose control (as chromium potentiates insulin).

53. A 40-year-old alcoholic man has cracks at the corners of his mouth, a magenta-colored tongue, and a rash. He also has corneal neovascularization. These findings suggest a deficiency of:
    A. Vitamin B1 (thiamine)
    B. Vitamin B3 (niacin)
    C. Vitamin B6 (pyridoxine)
    D. Vitamin B2 (riboflavin)
    E. Vitamin B12 (cobalamin)

    Explanation: The correct answer is D. Riboflavin (B2) deficiency causes angular cheilitis (fissures at mouth corners), glossitis (inflamed tongue that can appear magenta), seborrheic dermatitis, and corneal vascularization. Riboflavin is a component of FAD and FMN, used in redox reactions. Alcoholics and severely malnourished individuals are at risk.
    Choice A: Thiamine deficiency causes Wernicke-Korsakoff or beriberi (neuropathy, cardiac failure).
    Choice B: Niacin deficiency causes pellagra (dermatitis, diarrhea, dementia).
    Choice C: Pyridoxine deficiency can cause cheilosis and glossitis too, but also peripheral neuropathy and sideroblastic anemia; corneal neovascularization is more specific to riboflavin.
    Choice E: B12 deficiency causes macrocytic anemia and neurologic deficits.

54. A 10-year-old Ashkenazi Jewish boy has fatigue and bone pain. He has massive hepatosplenomegaly and pancytopenia. Imaging shows avascular necrosis of the femoral head. Bone marrow biopsy reveals macrophages filled with lipid with a “crinkled tissue paper” appearance. Which enzyme is most likely deficient?
    A. α-Galactosidase A
    B. Glucocerebrosidase (β-glucosidase)
    C. Sphingomyelinase
    D. Hexosaminidase A
    E. Arylsulfatase A

    Explanation: The correct answer is B. This is Gaucher disease, the most common lysosomal storage disease, due to glucocerebrosidase (β-glucosidase) deficiency. Glucocerebroside accumulates in macrophages (Gaucher cells) that look like crumpled tissue paper. Findings include hepatosplenomegaly, pancytopenia, bone pain/crisis, osteoporosis, and aseptic necrosis of femur. It is especially prevalent in Ashkenazi Jews and has an autosomal recessive inheritance; enzyme replacement is available.
    Choice A: α-Galactosidase A deficiency causes Fabry disease (angiokeratomas, renal failure, neuropathy).
    Choice C: Sphingomyelinase deficiency causes Niemann-Pick (neurodegeneration, cherry-red spot, hepatosplenomegaly).
    Choice D: Hexosaminidase A deficiency causes Tay-Sachs (neurodegeneration, cherry-red spot, no hepatosplenomegaly).
    Choice E: Arylsulfatase A deficiency causes metachromatic leukodystrophy (demyelination, ataxia, dementia).

55. A 52-year-old man has been taking megadose vitamin supplements. He now has confusion, constipation, and increased urination. Labs show hypercalcemia and elevated 1,25-dihydroxyvitamin D; he also developed kidney stones. What is the most likely cause of his findings?
    A. Excess vitamin D intake (hypervitaminosis D)
    B. Primary hyperparathyroidism
    C. Vitamin A toxicity
    D. PTH-related peptide from malignancy
    E. Thiazide diuretic use

    Explanation: The correct answer is A. Vitamin D toxicity can cause hypercalcemia (leading to confusion, polyuria/polydipsia, constipation, kidney stones) and elevated active vitamin D levels. It often results from excessive supplementation. Hypercalcemia from vitamin D triggers increased bone resorption and intestinal calcium absorption.
    Choice B: Primary hyperparathyroidism (like a parathyroid adenoma) causes hypercalcemia, but vitamin D levels wouldn’t be high; PTH would be high instead.
    Choice C: Hypervitaminosis A causes intracranial hypertension, skin changes, and liver toxicity, not primarily hypercalcemia.
    Choice D: PTHrP from malignancy (humoral hypercalcemia of malignancy) causes hypercalcemia with suppressed PTH and low vitamin D levels (since PTHrP doesn’t raise vitamin D).
    Choice E: Thiazides can cause mild hypercalcemia by increased renal calcium reabsorption, but not the very high calcium with elevated 1,25-(OH)2 D seen here.

56. A 3-year-old girl has hepatomegaly and mild fasting hypoglycemia that improves with frequent meals. Unlike the more severe Type I glycogen storage disease, her blood lactate is normal. Liver biopsy shows accumulation of glycogen with very short outer chains. Which enzyme is most likely deficient?
    A. Glucose-6-phosphatase
    B. Lysosomal acid α-1,4-glucosidase
    C. Muscle glycogen phosphorylase
    D. Debranching enzyme (α-1,6-glucosidase)
    E. Galactose-1-phosphate uridyltransferase

    Explanation: The correct answer is D. This is Cori disease (Type III GSD), caused by a deficiency of the debranching enzyme. It leads to hepatomegaly, ketotic hypoglycemia (milder than Von Gierke), normal blood lactate (gluconeogenesis intact), and glycogen with short outer branches (limit dextrin-like structures).
    Choice A: Glucose-6-phosphatase deficiency is Von Gierke disease (Type I) – more severe hypoglycemia with lactic acidosis and hyperuricemia.
    Choice B: Lysosomal α-1,4-glucosidase (acid maltase) deficiency is Pompe disease (Type II) – cardiomegaly and hypotonia.
    Choice C: Muscle glycogen phosphorylase deficiency is McArdle disease (Type V) – exercise intolerance, muscle cramps.
    Choice E: Galactose-1-P uridyltransferase deficiency causes classic galactosemia – not a glycogen storage disease.

57. A 6-month-old boy has fructose detected in his urine during a routine exam, but he shows no symptoms and his blood glucose remains normal even after feeding fructose. He is otherwise healthy. What is the most likely condition?
    A. Essential fructosuria
    B. Hereditary fructose intolerance
    C. Classic galactosemia
    D. Diabetes mellitus
    E. Fanconi syndrome

    Explanation: The correct answer is A. Essential fructosuria is a benign condition due to fructokinase deficiency. Fructose is not properly metabolized in the liver and spills into urine, but it causes no symptoms (fructose isn’t trapped in cells, and an alternative pathway via hexokinase metabolizes some fructose). Patients have reducing sugar in urine that is not glucose, but normal blood glucose levels.
    Choice B: Hereditary fructose intolerance (aldolase B deficiency) is symptomatic with hypoglycemia, vomiting, and liver damage after fructose ingestion.
    Choice C: Classic galactosemia (GALT deficiency) causes serious illness in neonates with feeding (milk) – not an asymptomatic fructosuria.
    Choice D: Diabetes causes glucose (not fructose) in urine, with hyperglycemia and symptoms.
    Choice E: Fanconi syndrome (proximal tubule dysfunction) causes generalized loss of many substances (glucose, amino acids, phosphate) in urine with failure to thrive; isolated fructosuria in a well infant points to essential fructosuria.

58. A 30-year-old battery factory worker has abdominal pain, fatigue, and a peripheral neuropathy (wrist drop). Lab shows microcytic anemia with basophilic stippling of RBCs. Lead poisoning interferes with heme synthesis by inhibiting:
    A. Uroporphyrinogen decarboxylase
    B. δ-ALA synthase
    C. Porphobilinogen deaminase
    D. Ferrochelatase (and ALA dehydratase)
    E. Beta-globin chain synthesis

    Explanation: The correct answer is D. Lead inhibits ferrochelatase and ALA dehydratase in the heme synthesis pathway. Ferrochelatase is the final enzyme that inserts iron into protoporphyrin IX; its inhibition leads to accumulation of protoporphyrin and causes microcytic, hypochromic anemia with basophilic stippling. ALA dehydratase inhibition leads to elevated δ-ALA levels.
    Choice A: Uroporphyrinogen decarboxylase deficiency causes porphyria cutanea tarda (photosensitivity, tea-colored urine).
    Choice B: δ-ALA synthase is the first enzyme in heme synthesis (rate-limiting); it’s actually upregulated in certain conditions (e.g., sideroblastic anemia with B6 deficiency), not inhibited by lead.
    Choice C: Porphobilinogen deaminase deficiency causes acute intermittent porphyria (abdominal pain, neuro symptoms, but no anemia).
    Choice E: Impaired beta-globin synthesis is thalassemia, not the mechanism of lead poisoning.

59. A 23-year-old man develops hand tremors, difficulty speaking, and involuntary movements. He also shows signs of cirrhosis. On exam, there are brownish rings at the corneal periphery. These findings are most suggestive of:
    A. Hereditary hemochromatosis
    B. Wilson disease
    C. α-1 antitrypsin deficiency
    D. Primary biliary cholangitis
    E. Menkes disease

    Explanation: The correct answer is B. Wilson disease (hepatolenticular degeneration) is due to a mutation in the ATP7B gene leading to impaired copper excretion in bile and incorporation into ceruloplasmin. Copper accumulates in liver (causing cirrhosis) and brain (basal ganglia, causing movement disorders and dysarthria), and in the corneas as Kayser-Fleischer rings. It often presents in young adults. Treatment is with copper chelators (e.g., penicillamine).
    Choice A: Hemochromatosis (iron overload) presents later with cirrhosis, diabetes, skin bronzing, and heart disease; it doesn’t cause K-F rings or early neuro symptoms.
    Choice C: α-1 antitrypsin deficiency can cause early emphysema and cirrhosis, but not neuro symptoms or K-F rings.
    Choice D: Primary biliary cholangitis is an autoimmune liver disease (intrahepatic bile duct destruction) in middle-aged women, with cholestasis and pruritus, not neuro symptoms or K-F rings.
    Choice E: Menkes disease is a copper transport disorder (ATP7A) causing copper deficiency in infancy (kinky hair, neuro deterioration), opposite of Wilson’s copper overload in young adulthood.

60. A 6-month-old boy has developmental delay, hypotonia, and frequent seizures. His hair is sparse, short, and kinky. He is failing to thrive and has low body temperature. Lab shows low copper levels. What is the most likely diagnosis?
    A. Wilson disease
    B. Kwashiorkor
    C. Menkes disease
    D. Hurler syndrome
    E. Phenylketonuria

    Explanation: The correct answer is C. This is Menkes disease, an X-linked recessive disorder of copper transport due to an ATP7A gene mutation. It leads to impaired intestinal copper absorption and low copper availability. Infants present with growth failure, developmental delay, hypotonia, seizures, and brittle, “kinky” hair. Copper is a cofactor for lysyl oxidase, so connective tissue is also affected. Without treatment (copper histidine injections), it is often fatal in childhood.
    Choice A: Wilson disease is copper overload (opposite problem) presenting later with liver and neuro symptoms and K-F rings.
    Choice B: Kwashiorkor is protein malnutrition (edema, fatty liver) in older infants/children, not applicable here.
    Choice D: Hurler syndrome is a lysosomal storage disease with coarse facial features, corneal clouding, hepatosplenomegaly, not the hair and copper findings here.
    Choice E: PKU presents with intellectual disability and musty odor, but normal hair; also, PKU is managed by diet and not typically associated with seizures if treated from birth.