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NBME CBSE USMLE Step 1 Actual Test Questions &
Answers 2025/2026,100% CORRECT ALREADY RATED
A+
Q1
A 6-month-old infant presents with poor feeding, hypotonia, seizures, and elevated
lactate on blood gas. Genetic testing shows a defect in the E1 subunit of a
mitochondrial multienzyme complex. Which of the following metabolic
abnormalities best explains the lactic acidosis in this condition?
A. Impaired conversion of pyruvate to oxaloacetate
B. Impaired conversion of pyruvate to acetyl-CoA (E1 of PDH complex
defective)
C. Increased conversion of lactate to pyruvate
D. Increased flux through pyruvate carboxylase
E. Increased activity of pyruvate dehydrogenase kinase
Correct answer: B.
Rationale: The E1 subunit is part of the pyruvate dehydrogenase (PDH) complex,
which converts pyruvate into acetyl-CoA for entry into the TCA cycle. A defect
reduces acetyl-CoA production and shunts pyruvate toward lactate via lactate
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dehydrogenase, causing lactic acidosis. Choice E (increased PDH kinase) would
also inactivate PDH and produce lactic acidosis — mechanistically similar — but
the vignette specifically notes a structural defect in E1 (PDH deficiency), making
B the best choice. Choice A describes pyruvate carboxylase (pyruvate →
oxaloacetate), not the PDH complex. Choice C (increased lactate→pyruvate)
would lower lactate. Choice D (increased pyruvate carboxylase) would favor
gluconeogenesis/oxaloacetate, not explain lactic acidosis.
Test tip: PDH deficiency → lactic acidosis, neurological findings; treat with
ketogenic diet (increase fat to provide acetyl-CoA).
Q2
A 4-year-old child is evaluated for developmental delay and microcytic anemia.
Labs reveal basophilic stippling and elevated free erythrocyte protoporphyrin.
Occupational history reveals pica and chalk ingestion. Which enzyme is most
likely inhibited by the toxic agent responsible?
A. Uroporphyrinogen decarboxylase
B. Ferrochelatase
C. ALA dehydratase (porphobilinogen synthase)
D. Porphobilinogen deaminase
E. Delta-aminolevulinic acid synthase (ALAS)
Correct answer: C.
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Rationale: Lead inhibits ALA dehydratase (also called porphobilinogen synthase)
and ferrochelatase, causing elevated ALA and protoporphyrin and basophilic
stippling. Among choices, ALA dehydratase inhibition best explains increased
ALA and the classical lead toxicity profile with neurodevelopmental problems and
anemia. Ferrochelatase (choice B) is also inhibited by lead; however, the more
sensitive early block is ALA dehydratase — NBME-style stems commonly test
ALA dehydratase inhibition. Choices A and D are more relevant to porphyria
cutanea tarda and acute intermittent porphyria, respectively. Choice E (ALAS) is
the rate-limiting enzyme and is not inhibited by lead.
Test tip: Lead poisoning → basophilic stippling, abdominal pain, neuro deficits;
treat with chelation (EDTA, succimer).
Q3
A 2-year-old with severe fasting hypoglycemia, lactic acidosis, doll-like facies, and
hepatomegaly is suspected of having von Gierke disease. Which enzyme
deficiency most likely explains the presentation?
A. Lysosomal acid maltase (alpha-1,4-glucosidase)
B. Debranching enzyme (amylo-1,6-glucosidase)
C. Glucose-6-phosphatase
D. Branching enzyme (glycogen-branching enzyme)
E. Glycogen phosphorylase
Correct answer: C.
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Rationale: Von Gierke disease (GSD type I) is due to glucose-6-phosphatase
deficiency, leading to inability to produce free glucose from G6P → severe fasting
hypoglycemia, lactic acidosis (pyruvate shunted to lactate), hyperuricemia, and
hyperlipidemia; hepatomegaly occurs from glycogen accumulation. Choice A
(Pompe disease) causes cardiomyopathy and muscle weakness. Choice B (Cori
disease) gives milder hypoglycemia with normal lactate. Choice D (Andersen
disease) causes abnormal branching and progressive cirrhosis. Choice E (McArdle)
causes exercise intolerance and myoglobinuria, not severe fasting hypoglycemia.
Test tip: GSD I → severe fasting hypoglycemia + lactic acidosis.
Q4
A male infant is found to have short stature, recurrent infections, and failure to
thrive. Genetic testing reveals a mutation in a DNA mismatch repair gene leading
to microsatellite instability in somatic cells. Which hereditary cancer
predisposition syndrome is most closely associated with germline defects in
mismatch repair genes?
A. Lynch syndrome (hereditary nonpolyposis colorectal cancer)
B. Familial adenomatous polyposis (APC mutation)
C. BRCA1/2–associated hereditary breast/ovarian cancer
D. Li-Fraumeni syndrome (TP53)
E. Von Hippel-Lindau disease
Correct answer: A.
NBME CBSE USMLE Step 1 Actual Test Questions &
Answers 2025/2026,100% CORRECT ALREADY RATED
A+
Q1
A 6-month-old infant presents with poor feeding, hypotonia, seizures, and elevated
lactate on blood gas. Genetic testing shows a defect in the E1 subunit of a
mitochondrial multienzyme complex. Which of the following metabolic
abnormalities best explains the lactic acidosis in this condition?
A. Impaired conversion of pyruvate to oxaloacetate
B. Impaired conversion of pyruvate to acetyl-CoA (E1 of PDH complex
defective)
C. Increased conversion of lactate to pyruvate
D. Increased flux through pyruvate carboxylase
E. Increased activity of pyruvate dehydrogenase kinase
Correct answer: B.
Rationale: The E1 subunit is part of the pyruvate dehydrogenase (PDH) complex,
which converts pyruvate into acetyl-CoA for entry into the TCA cycle. A defect
reduces acetyl-CoA production and shunts pyruvate toward lactate via lactate
,2|Page
dehydrogenase, causing lactic acidosis. Choice E (increased PDH kinase) would
also inactivate PDH and produce lactic acidosis — mechanistically similar — but
the vignette specifically notes a structural defect in E1 (PDH deficiency), making
B the best choice. Choice A describes pyruvate carboxylase (pyruvate →
oxaloacetate), not the PDH complex. Choice C (increased lactate→pyruvate)
would lower lactate. Choice D (increased pyruvate carboxylase) would favor
gluconeogenesis/oxaloacetate, not explain lactic acidosis.
Test tip: PDH deficiency → lactic acidosis, neurological findings; treat with
ketogenic diet (increase fat to provide acetyl-CoA).
Q2
A 4-year-old child is evaluated for developmental delay and microcytic anemia.
Labs reveal basophilic stippling and elevated free erythrocyte protoporphyrin.
Occupational history reveals pica and chalk ingestion. Which enzyme is most
likely inhibited by the toxic agent responsible?
A. Uroporphyrinogen decarboxylase
B. Ferrochelatase
C. ALA dehydratase (porphobilinogen synthase)
D. Porphobilinogen deaminase
E. Delta-aminolevulinic acid synthase (ALAS)
Correct answer: C.
,3|Page
Rationale: Lead inhibits ALA dehydratase (also called porphobilinogen synthase)
and ferrochelatase, causing elevated ALA and protoporphyrin and basophilic
stippling. Among choices, ALA dehydratase inhibition best explains increased
ALA and the classical lead toxicity profile with neurodevelopmental problems and
anemia. Ferrochelatase (choice B) is also inhibited by lead; however, the more
sensitive early block is ALA dehydratase — NBME-style stems commonly test
ALA dehydratase inhibition. Choices A and D are more relevant to porphyria
cutanea tarda and acute intermittent porphyria, respectively. Choice E (ALAS) is
the rate-limiting enzyme and is not inhibited by lead.
Test tip: Lead poisoning → basophilic stippling, abdominal pain, neuro deficits;
treat with chelation (EDTA, succimer).
Q3
A 2-year-old with severe fasting hypoglycemia, lactic acidosis, doll-like facies, and
hepatomegaly is suspected of having von Gierke disease. Which enzyme
deficiency most likely explains the presentation?
A. Lysosomal acid maltase (alpha-1,4-glucosidase)
B. Debranching enzyme (amylo-1,6-glucosidase)
C. Glucose-6-phosphatase
D. Branching enzyme (glycogen-branching enzyme)
E. Glycogen phosphorylase
Correct answer: C.
, 4|Page
Rationale: Von Gierke disease (GSD type I) is due to glucose-6-phosphatase
deficiency, leading to inability to produce free glucose from G6P → severe fasting
hypoglycemia, lactic acidosis (pyruvate shunted to lactate), hyperuricemia, and
hyperlipidemia; hepatomegaly occurs from glycogen accumulation. Choice A
(Pompe disease) causes cardiomyopathy and muscle weakness. Choice B (Cori
disease) gives milder hypoglycemia with normal lactate. Choice D (Andersen
disease) causes abnormal branching and progressive cirrhosis. Choice E (McArdle)
causes exercise intolerance and myoglobinuria, not severe fasting hypoglycemia.
Test tip: GSD I → severe fasting hypoglycemia + lactic acidosis.
Q4
A male infant is found to have short stature, recurrent infections, and failure to
thrive. Genetic testing reveals a mutation in a DNA mismatch repair gene leading
to microsatellite instability in somatic cells. Which hereditary cancer
predisposition syndrome is most closely associated with germline defects in
mismatch repair genes?
A. Lynch syndrome (hereditary nonpolyposis colorectal cancer)
B. Familial adenomatous polyposis (APC mutation)
C. BRCA1/2–associated hereditary breast/ovarian cancer
D. Li-Fraumeni syndrome (TP53)
E. Von Hippel-Lindau disease
Correct answer: A.
