NBME CBSE / USMLE Step 1 Qbank (2026/2027) (200 Questions with Comprehensive
Explanations)
BIOCHEMISTRY & GENETICS (Questions 1-40)
1. A 4-day-old boy is brought to the emergency department with lethargy, poor feeding, and
jaundice. Laboratory studies show hypoglycemia, elevated blood lactate, and increased
urinary 4-hydroxyphenyllactate. Skin fibroblast enzyme assay demonstrates deficient
activity of dihydropteridine reductase (DHPR). Which of the following best explains why
dietary phenylalanine restriction alone will NOT prevent neurologic deterioration in this
patient?
A) Tyrosine becomes an essential amino acid
B) Dopamine and serotonin synthesis are impaired in the brain
C) Branched-chain amino acids accumulate systemically
D) Tetrahydrobiopterin is overproduced in liver mitochondria
E) Gluconeogenesis is irreversibly blocked in hepatocytes
Correct Answer: B
Explanation: DHPR deficiency causes a rare "malignant" form of phenylketonuria in which
tetrahydrobiopterin (BH4), the obligate cofactor for phenylalanine hydroxylase, cannot be
regenerated. Consequently BH4 is also unavailable to brain tyrosine and tryptophan
hydroxylases, so dopamine and serotonin synthesis collapse despite dietary phenylalanine
restriction, leading to irreversible neurotransmitter deficiency and neurologic decline (choice B).
Tyrosine is already essential in classic PKU (choice A) but is not the primary driver of CNS
injury here. BCAA elevation (choice C) is seen in maple-syrup-urine disease, BH4 is under-
produced not over-produced (choice D), and gluconeogenesis is intact (choice E).
2. A 25-year-old woman with a strong family history of early myocardial infarction is found
to have an LDL-cholesterol of 410 mg/dL. Molecular analysis shows homozygosity for a
missense mutation in exon 4 of the LDL-receptor gene that encodes the ligand-binding
domain. Which of the following intracellular events is most directly impaired in
hepatocytes of this patient?
A) Clathrin-mediated endocytosis of apoB-100-containing particles
B) Lysosomal degradation of cholesteryl esters
C) Release of free cholesterol from late endosomes
D) Proteasomal degradation of HMG-CoA reductase
E) SREBP-2 activation in the Golgi
Correct Answer: A
Explanation: The described mutation produces classic homozygous familial
hypercholesterolemia. A defective ligand-binding domain prevents the LDL receptor from
clustering into clathrin-coated pits, so hepatocytes cannot perform receptor-mediated endocytosis
of LDL particles (choice A). Lysosomal hydrolysis (choice B) and NPC1-mediated cholesterol
release (choice C) occur normally once internalization happens. HMG-CoA reductase
degradation (choice D) and SREBP-2 processing (choice E) are downstream of intracellular
,cholesterol sensing and are actually up-regulated because LDL-derived cholesterol delivery is
low.
3. A 6-year-old girl develops acute hemolytic anemia after eating fava beans. Peripheral-
blood smear shows Heinz bodies and bite cells. Glucose-6-phosphate dehydrogenase
(G6PD) activity is 5 % of normal. Which metabolic intermediate accumulates and drives
oxidative damage to hemoglobin in this patient?
A) Glucose-6-phosphate
B) 6-Phosphogluconate
C) Ribulose-5-phosphate
D) NADP+
E) Hydrogen peroxide
Correct Answer: E
Explanation: G6PD deficiency impairs the pentose-phosphate pathway, decreasing NADPH
production. Low NADPH prevents glutathione reductase from maintaining reduced glutathione
(GSH), so hydrogen peroxide and other reactive oxygen species generated during drug or fava-
bean stress are not detoxified (choice E). Accumulated H₂O₂ oxidizes hemoglobin iron,
producing Heinz bodies and hemolysis. Glucose-6-phosphate (choice A) levels are normal, 6-
phosphogluconate (choice B) and ribulose-5-phosphate (choice C) are downstream intermediates
that do not cause oxidative injury, and NADP+ (choice D) is the oxidized cofactor that actually
accumulates but does not directly damage hemoglobin.
4. A 2-week-old infant is hypotonic and feeds poorly. Serum creatine kinase is markedly
elevated. Muscle biopsy shows absent dystrophin on immunostaining. Which of the
following best explains why female carriers of this X-linked disorder are usually
asymptomatic?
A) Random X-inactivation creates a mosaic with ≥50 % normal myofibers
B) Dystrophin is up-regulated on the active X chromosome
C) Autosomal duplication compensates for the mutant allele
D) Skewed inactivation always selects the normal X
E) Mitochondrial genes provide redundant function
Correct Answer: A
Explanation: Duchenne muscular dystrophy results from loss-of-function mutations in
dystrophin on the X chromosome. In females, random (lyonization) X-inactivation produces a
mosaic: approximately half of myofibers express normal dystrophin from the active wild-type X,
providing enough structural support to prevent clinical symptoms (choice A). Up-regulation
(choice B) and autosomal duplication (choice C) do not occur. Skewing (choice D) is not
obligatory, and mitochondrial genes (choice E) do not compensate for sarcolemmal stability.
5. A 30-year-old man with chronic kidney disease receives recombinant human
erythropoietin. Which post-translational modification of the hormone is essential for its
in-vivo biologic activity?
A) γ-Carboxylation of glutamate residues
, B) N-linked glycosylation
C) Phosphorylation of tyrosine residues
D) Prenylation of cysteine residues
E) Sulfation of tyrosine residues
Correct Answer: B
Explanation: Erythropoietin is a heavily glycosylated protein; terminal sialic acid on its N-linked
oligosaccharides protects the hormone from hepatic galactose-receptor uptake and renal
filtration, prolonging serum half-life. Hypoglycosylated EPO is rapidly cleared and ineffective
(choice B). γ-Carboxylation (choice A) is for clotting factors, tyrosine phosphorylation (choice
C) is a signaling event not a modification of the hormone itself, prenylation (choice D) targets
membrane proteins, and sulfation (choice E) is common for pituitary hormones but not critical
for EPO activity.
6. A 45-year-old woman develops progressive dementia, behavioral changes, and
choreiform movements. Family history is positive for similar neuropsychiatric disease in
her father and paternal uncle, with onset in the fifth decade. PCR amplification across the
IT-15 gene shows 46 CAG repeats. Which molecular mechanism best explains neuronal
dysfunction in this patient?
A) Loss of function of huntingtin protein
B) Toxic gain of function of mutant huntingtin fragment
C) Impaired ribosomal frameshifting
D) Decreased transcription of downstream genes
E) Aberrant mRNA splicing
Correct Answer: B
Explanation: Huntington disease is caused by expansion of a CAG trinucleotide repeat (>36) in
the huntingtin gene, encoding an abnormally long polyglutamine tract. The mutant protein is
cleaved into N-terminal fragments that misfold, aggregate in nuclei, and exert a toxic gain-of-
function effect on transcription, proteostasis, and mitochondrial dynamics (choice B). It is not a
simple loss-of-function (choice A), nor are ribosomal frameshifting (choice C), transcriptional
read-through (choice D), or splicing defects (choice E) the primary pathogenic events.
7. A 16-year-old girl presents with primary amenorrhea. Breast development is Tanner stage
III, but she has no axillary or pubic hair. Pelvic ultrasound shows a blind-ending vaginal
pouch and absent uterus. Serum testosterone is in the high-normal male range. Which
enzymatic step is defective?
A) 17α-hydroxylase
B) 21β-hydroxylase
C) 11β-hydroxylase
D) 5α-reductase
E) Aromatase
Correct Answer: D
Explanation: The phenotype—46,XY karyotype (implied by male-level testosterone), absent
, müllerian structures (no uterus), and impaired virilization (no pubic/axillary hair, blind vagina)
despite adequate testosterone—characterizes 5α-reductase deficiency (choice D). Lack of
dihydrotestosterone (DHT) prevents external genital masculinization and androgen-dependent
hair growth while testes-derived anti-müllerian hormone regresss müllerian ducts. 17α-
hydroxylase deficiency (choice A) would cause low androgens and hypertension; 21- and 11β-
hydroroxylase (choices B, C) produce ambiguous genitalia with salt-wasting or virilization;
aromatase deficiency (choice E) would not impair androgen action.
8. A 4-year-old boy has episodes of hypoglycemia and elevated ammonia after minor
illnesses. Plasma alanine is high, and ketone bodies are present. Which enzyme defect
links both hypoglycemia and hyperammonemia in this child?
A) Carnitine palmitoyl-transferase I
B) Medium-chain acyl-CoA dehydrogenase (MCAD)
C) Pyruvate carboxylase
D) Glycogen synthase
E) Glutaminase
Correct Answer: C
Explanation: Pyruvate carboxylase (PC) catalyzes the anaplerotic conversion of pyruvate to
oxaloacetate, essential for gluconeogenesis and for replenishing Krebs-cycle intermediates that
accept acetyl-CoA from fatty-acid oxidation. PC deficiency (choice C) causes fasting
hypoglycemia (impaired gluconeogenesis) and accumulation of pyruvate, which is transaminated
to alanine (high plasma alanine) and shunted to ketone-body formation. Low oxaloacetate
reduces citrate synthesis, leading to buildup of acetyl-CoA and hyperketosis. Additionally,
without adequate Krebs-cycle flux, glutamate-derived carbamoyl-phosphate cannot be consumed
for citrulline synthesis and instead enters the cytosol, driving hyperammonemia. MCAD
deficiency (choice B) causes hypoketotic hypoglycemia without hyperammonemia, CPT-I
(choice A) blocks long-chain FAO, glycogen synthase (choice D) causes glycogen storage
disease, and glutaminase (choice E) would lower, not raise, ammonia.
9. A 35-year-old man with gout has recurrent kidney stones composed of 2,8-
dihydroxyadenine. Genetic analysis reveals homozygosity for a missense variant in the
APRT gene. Which of the following best describes the metabolic derangement in this
patient?
A) Overproduction of uric acid due to PRPP synthetase superactivity
B) Inability to salvage adenine → adenine is oxidized to dihydroxyadenine
C) Accelerated purine degradation to uric acid
D) Defective urea cycle causing accumulation of adenine
E) Increased adenosine deaminase activity
Correct Answer: B
Explanation: Adenine phosphoribosyltransferase (APRT) catalyzes the salvage of adenine to
AMP using PRPP. APRT deficiency (choice B) forces adenine to be oxidized by xanthine
oxidase to 2,8-dihydroxyadenine, a poorly soluble compound that precipitates as urinary crystals
and stones. Unlike uric acid stones, these are radiolucent and do not respond to allopurinol unless
Explanations)
BIOCHEMISTRY & GENETICS (Questions 1-40)
1. A 4-day-old boy is brought to the emergency department with lethargy, poor feeding, and
jaundice. Laboratory studies show hypoglycemia, elevated blood lactate, and increased
urinary 4-hydroxyphenyllactate. Skin fibroblast enzyme assay demonstrates deficient
activity of dihydropteridine reductase (DHPR). Which of the following best explains why
dietary phenylalanine restriction alone will NOT prevent neurologic deterioration in this
patient?
A) Tyrosine becomes an essential amino acid
B) Dopamine and serotonin synthesis are impaired in the brain
C) Branched-chain amino acids accumulate systemically
D) Tetrahydrobiopterin is overproduced in liver mitochondria
E) Gluconeogenesis is irreversibly blocked in hepatocytes
Correct Answer: B
Explanation: DHPR deficiency causes a rare "malignant" form of phenylketonuria in which
tetrahydrobiopterin (BH4), the obligate cofactor for phenylalanine hydroxylase, cannot be
regenerated. Consequently BH4 is also unavailable to brain tyrosine and tryptophan
hydroxylases, so dopamine and serotonin synthesis collapse despite dietary phenylalanine
restriction, leading to irreversible neurotransmitter deficiency and neurologic decline (choice B).
Tyrosine is already essential in classic PKU (choice A) but is not the primary driver of CNS
injury here. BCAA elevation (choice C) is seen in maple-syrup-urine disease, BH4 is under-
produced not over-produced (choice D), and gluconeogenesis is intact (choice E).
2. A 25-year-old woman with a strong family history of early myocardial infarction is found
to have an LDL-cholesterol of 410 mg/dL. Molecular analysis shows homozygosity for a
missense mutation in exon 4 of the LDL-receptor gene that encodes the ligand-binding
domain. Which of the following intracellular events is most directly impaired in
hepatocytes of this patient?
A) Clathrin-mediated endocytosis of apoB-100-containing particles
B) Lysosomal degradation of cholesteryl esters
C) Release of free cholesterol from late endosomes
D) Proteasomal degradation of HMG-CoA reductase
E) SREBP-2 activation in the Golgi
Correct Answer: A
Explanation: The described mutation produces classic homozygous familial
hypercholesterolemia. A defective ligand-binding domain prevents the LDL receptor from
clustering into clathrin-coated pits, so hepatocytes cannot perform receptor-mediated endocytosis
of LDL particles (choice A). Lysosomal hydrolysis (choice B) and NPC1-mediated cholesterol
release (choice C) occur normally once internalization happens. HMG-CoA reductase
degradation (choice D) and SREBP-2 processing (choice E) are downstream of intracellular
,cholesterol sensing and are actually up-regulated because LDL-derived cholesterol delivery is
low.
3. A 6-year-old girl develops acute hemolytic anemia after eating fava beans. Peripheral-
blood smear shows Heinz bodies and bite cells. Glucose-6-phosphate dehydrogenase
(G6PD) activity is 5 % of normal. Which metabolic intermediate accumulates and drives
oxidative damage to hemoglobin in this patient?
A) Glucose-6-phosphate
B) 6-Phosphogluconate
C) Ribulose-5-phosphate
D) NADP+
E) Hydrogen peroxide
Correct Answer: E
Explanation: G6PD deficiency impairs the pentose-phosphate pathway, decreasing NADPH
production. Low NADPH prevents glutathione reductase from maintaining reduced glutathione
(GSH), so hydrogen peroxide and other reactive oxygen species generated during drug or fava-
bean stress are not detoxified (choice E). Accumulated H₂O₂ oxidizes hemoglobin iron,
producing Heinz bodies and hemolysis. Glucose-6-phosphate (choice A) levels are normal, 6-
phosphogluconate (choice B) and ribulose-5-phosphate (choice C) are downstream intermediates
that do not cause oxidative injury, and NADP+ (choice D) is the oxidized cofactor that actually
accumulates but does not directly damage hemoglobin.
4. A 2-week-old infant is hypotonic and feeds poorly. Serum creatine kinase is markedly
elevated. Muscle biopsy shows absent dystrophin on immunostaining. Which of the
following best explains why female carriers of this X-linked disorder are usually
asymptomatic?
A) Random X-inactivation creates a mosaic with ≥50 % normal myofibers
B) Dystrophin is up-regulated on the active X chromosome
C) Autosomal duplication compensates for the mutant allele
D) Skewed inactivation always selects the normal X
E) Mitochondrial genes provide redundant function
Correct Answer: A
Explanation: Duchenne muscular dystrophy results from loss-of-function mutations in
dystrophin on the X chromosome. In females, random (lyonization) X-inactivation produces a
mosaic: approximately half of myofibers express normal dystrophin from the active wild-type X,
providing enough structural support to prevent clinical symptoms (choice A). Up-regulation
(choice B) and autosomal duplication (choice C) do not occur. Skewing (choice D) is not
obligatory, and mitochondrial genes (choice E) do not compensate for sarcolemmal stability.
5. A 30-year-old man with chronic kidney disease receives recombinant human
erythropoietin. Which post-translational modification of the hormone is essential for its
in-vivo biologic activity?
A) γ-Carboxylation of glutamate residues
, B) N-linked glycosylation
C) Phosphorylation of tyrosine residues
D) Prenylation of cysteine residues
E) Sulfation of tyrosine residues
Correct Answer: B
Explanation: Erythropoietin is a heavily glycosylated protein; terminal sialic acid on its N-linked
oligosaccharides protects the hormone from hepatic galactose-receptor uptake and renal
filtration, prolonging serum half-life. Hypoglycosylated EPO is rapidly cleared and ineffective
(choice B). γ-Carboxylation (choice A) is for clotting factors, tyrosine phosphorylation (choice
C) is a signaling event not a modification of the hormone itself, prenylation (choice D) targets
membrane proteins, and sulfation (choice E) is common for pituitary hormones but not critical
for EPO activity.
6. A 45-year-old woman develops progressive dementia, behavioral changes, and
choreiform movements. Family history is positive for similar neuropsychiatric disease in
her father and paternal uncle, with onset in the fifth decade. PCR amplification across the
IT-15 gene shows 46 CAG repeats. Which molecular mechanism best explains neuronal
dysfunction in this patient?
A) Loss of function of huntingtin protein
B) Toxic gain of function of mutant huntingtin fragment
C) Impaired ribosomal frameshifting
D) Decreased transcription of downstream genes
E) Aberrant mRNA splicing
Correct Answer: B
Explanation: Huntington disease is caused by expansion of a CAG trinucleotide repeat (>36) in
the huntingtin gene, encoding an abnormally long polyglutamine tract. The mutant protein is
cleaved into N-terminal fragments that misfold, aggregate in nuclei, and exert a toxic gain-of-
function effect on transcription, proteostasis, and mitochondrial dynamics (choice B). It is not a
simple loss-of-function (choice A), nor are ribosomal frameshifting (choice C), transcriptional
read-through (choice D), or splicing defects (choice E) the primary pathogenic events.
7. A 16-year-old girl presents with primary amenorrhea. Breast development is Tanner stage
III, but she has no axillary or pubic hair. Pelvic ultrasound shows a blind-ending vaginal
pouch and absent uterus. Serum testosterone is in the high-normal male range. Which
enzymatic step is defective?
A) 17α-hydroxylase
B) 21β-hydroxylase
C) 11β-hydroxylase
D) 5α-reductase
E) Aromatase
Correct Answer: D
Explanation: The phenotype—46,XY karyotype (implied by male-level testosterone), absent
, müllerian structures (no uterus), and impaired virilization (no pubic/axillary hair, blind vagina)
despite adequate testosterone—characterizes 5α-reductase deficiency (choice D). Lack of
dihydrotestosterone (DHT) prevents external genital masculinization and androgen-dependent
hair growth while testes-derived anti-müllerian hormone regresss müllerian ducts. 17α-
hydroxylase deficiency (choice A) would cause low androgens and hypertension; 21- and 11β-
hydroroxylase (choices B, C) produce ambiguous genitalia with salt-wasting or virilization;
aromatase deficiency (choice E) would not impair androgen action.
8. A 4-year-old boy has episodes of hypoglycemia and elevated ammonia after minor
illnesses. Plasma alanine is high, and ketone bodies are present. Which enzyme defect
links both hypoglycemia and hyperammonemia in this child?
A) Carnitine palmitoyl-transferase I
B) Medium-chain acyl-CoA dehydrogenase (MCAD)
C) Pyruvate carboxylase
D) Glycogen synthase
E) Glutaminase
Correct Answer: C
Explanation: Pyruvate carboxylase (PC) catalyzes the anaplerotic conversion of pyruvate to
oxaloacetate, essential for gluconeogenesis and for replenishing Krebs-cycle intermediates that
accept acetyl-CoA from fatty-acid oxidation. PC deficiency (choice C) causes fasting
hypoglycemia (impaired gluconeogenesis) and accumulation of pyruvate, which is transaminated
to alanine (high plasma alanine) and shunted to ketone-body formation. Low oxaloacetate
reduces citrate synthesis, leading to buildup of acetyl-CoA and hyperketosis. Additionally,
without adequate Krebs-cycle flux, glutamate-derived carbamoyl-phosphate cannot be consumed
for citrulline synthesis and instead enters the cytosol, driving hyperammonemia. MCAD
deficiency (choice B) causes hypoketotic hypoglycemia without hyperammonemia, CPT-I
(choice A) blocks long-chain FAO, glycogen synthase (choice D) causes glycogen storage
disease, and glutaminase (choice E) would lower, not raise, ammonia.
9. A 35-year-old man with gout has recurrent kidney stones composed of 2,8-
dihydroxyadenine. Genetic analysis reveals homozygosity for a missense variant in the
APRT gene. Which of the following best describes the metabolic derangement in this
patient?
A) Overproduction of uric acid due to PRPP synthetase superactivity
B) Inability to salvage adenine → adenine is oxidized to dihydroxyadenine
C) Accelerated purine degradation to uric acid
D) Defective urea cycle causing accumulation of adenine
E) Increased adenosine deaminase activity
Correct Answer: B
Explanation: Adenine phosphoribosyltransferase (APRT) catalyzes the salvage of adenine to
AMP using PRPP. APRT deficiency (choice B) forces adenine to be oxidized by xanthine
oxidase to 2,8-dihydroxyadenine, a poorly soluble compound that precipitates as urinary crystals
and stones. Unlike uric acid stones, these are radiolucent and do not respond to allopurinol unless
