NBOME | COMSAE Comprehensive Examination
COMSAE Comprehensive Examination
2026/2027 | Verified Questions
National Board of Osteopathic Medical Examiners | COMSAE Comprehensive Examination | Professional
Osteopathic Medical Candidates
176 Verified Questions | 4 Core Domains | Academic Year 2026/2027
Prepared by
NBOME | COMSAE Comprehensive Examination
Comprehensive Licensing Examination Actual Exam | Academic Year 2026/2027
COMSAE Comprehensive Examination 2026/2027 | Verified Questions
,INTRODUCTION
This document contains exactly 176 original Medical-Level questions organized across four core domains: Domain
1, Foundational Biomedical Sciences (44); Domain 2, Osteopathic Principles and Practice (44); Domain 3, Clinical
Problem Solving and Patient Management (44); and Domain 4, Health Maintenance and Preventive Medicine (44).
The content integrates biomedical mechanisms, osteopathic diagnosis and treatment, clinical decision-making,
patient safety, and evidence-based prevention for the Comprehensive Licensing Examination aligned to Academic
Year 2026/2027.
ACTUAL QUESTIONS
Domain 1: Foundational Biomedical Sciences
Question 1. A reversible inhibitor competes with substrate for an enzyme's active site. Which
kinetic change is expected?
A. The apparent Km increases while Vmax remains unchanged.
B. The apparent Km decreases while Vmax increases.
C. Vmax decreases while Km remains unchanged.
D. Both Km and Vmax decrease to zero.
Correct Answer: A
Rationale: More substrate can overcome competitive inhibition, so the original maximal velocity remains
attainable. A higher substrate concentration is needed to reach half-maximal velocity, increasing the apparent
Km.
Question 2. A patient with metabolic acidosis has a bicarbonate concentration of 12 mEq/L and an
arterial carbon dioxide pressure of 40 mm Hg. Which interpretation is most accurate?
A. Respiratory compensation is appropriate.
B. A concurrent respiratory alkalosis is present.
C. A concurrent respiratory acidosis is present.
D. The values show isolated metabolic alkalosis.
Correct Answer: C
Rationale: Winter's relationship predicts a carbon dioxide pressure near 26 mm Hg, with a small expected
range, when bicarbonate is 12. A measured value of 40 is too high for compensation and indicates added
respiratory acidosis.
Question 3. A woman has a pathogenic mitochondrial DNA variant with high heteroplasmy. Which
inheritance pattern is expected?
A. The variant follows a strict autosomal recessive pattern.
B. All of her children may inherit the variant, but clinical severity can differ.
C. Only her sons can inherit the variant.
D. An affected father transmits the variant to every daughter.
Correct Answer: B
Rationale: Mitochondria in the embryo are derived predominantly from the oocyte, producing maternal
transmission. Heteroplasmy and replicative segregation cause variable organ involvement and severity among
offspring.
Question 4. Successive generations of a family develop a neurologic disorder at younger ages with
increasing severity. Which genetic mechanism best explains this pattern?
A. Random X chromosome inactivation alone
B. Loss of all mitochondrial DNA
C. Balanced reciprocal translocation without gene disruption
D. Expansion of a trinucleotide repeat
Correct Answer: D
Rationale: Unstable repeat expansion during gametogenesis can increase repeat length in later generations.
The larger expansion often produces earlier onset or greater severity, a pattern called anticipation.
COMSAE Comprehensive Examination 2026/2027 | Verified Questions
,Question 5. An autosomal recessive disease affects 1 in 10,000 people in a population at
equilibrium. Approximately what proportion of the population consists of carriers?
A. 1 in 5,000
B. 1 in 50
C. 1 in 100
D. 1 in 10,000
Correct Answer: B
Rationale: The affected frequency is q squared, so q is 0.01. The carrier frequency is approximately 2q when the
allele is rare, or about 0.02, which equals 1 in 50.
Question 6. A patient with severe dietary restriction has bleeding gums, perifollicular
hemorrhages, and poor wound healing. Which biochemical step is impaired?
A. Hydroxylation of proline and lysine residues in collagen
B. Oxidative deamination of dopamine
C. Gamma carboxylation of glutamate in clotting factors
D. Conversion of methylmalonyl-CoA to succinyl-CoA
Correct Answer: A
Rationale: Vitamin C is a cofactor for prolyl and lysyl hydroxylases in the endoplasmic reticulum. Impaired
hydroxylation weakens collagen triple helices and connective tissue integrity.
Question 7. A patient has macrocytic anemia, loss of vibration sense, and elevated methylmalonic
acid. Which deficiency is most likely?
A. Folate deficiency
B. Iron deficiency
C. Vitamin K deficiency
D. Vitamin B12 deficiency
Correct Answer: D
Rationale: Vitamin B12 is required for methylmalonyl-CoA metabolism and neurologic myelin maintenance.
Folate deficiency can cause megaloblastic anemia but does not raise methylmalonic acid or cause the
characteristic posterior-column findings.
Question 8. An infant has lactic acidosis and neurologic impairment due to pyruvate
dehydrogenase deficiency. Which dietary strategy can reduce reliance on the blocked pathway?
A. A diet composed only of simple glucose
B. High-dose fructose with no fat
C. A ketogenic diet rich in fat and low in carbohydrate
D. Elimination of all dietary protein and fat
Correct Answer: C
Rationale: Pyruvate cannot efficiently become acetyl-CoA, so carbohydrate use increases lactate. Ketone bodies
provide an alternative acetyl-CoA source for the brain and other tissues.
Question 9. A man develops jaundice and dark urine after receiving an oxidant medication. Blood
smear shows bite cells. Which defect is most likely?
A. Pyruvate kinase excess
B. Factor VIII deficiency
C. Hereditary elliptocytosis from collagen loss
D. Glucose-6-phosphate dehydrogenase deficiency
Correct Answer: D
Rationale: Reduced NADPH leaves erythrocytes unable to regenerate reduced glutathione during oxidative
stress. Denatured hemoglobin forms Heinz bodies that splenic macrophages remove, creating bite cells.
COMSAE Comprehensive Examination 2026/2027 | Verified Questions
, Question 10. A patient has anemia, jaundice, splenomegaly, spherocytes, and increased mean
corpuscular hemoglobin concentration. Which structural abnormality is most likely?
A. Reduced platelet glycoprotein IIb/IIIa
B. A defect in spectrin or ankyrin anchoring the red cell membrane
C. Absent beta-globin synthesis
D. Excess erythrocyte glucose-6-phosphate dehydrogenase
Correct Answer: B
Rationale: Loss of membrane surface area from cytoskeletal defects produces dense spherical erythrocytes with
poor deformability. Splenic sequestration causes extravascular hemolysis and explains why splenectomy
reduces anemia.
Question 11. A male neonate develops hyperammonemia, low blood urea nitrogen, and elevated
urinary orotic acid without megaloblastic anemia. Which enzyme is deficient?
A. Branched-chain alpha-ketoacid dehydrogenase
B. Orotate phosphoribosyltransferase
C. Ornithine transcarbamylase
D. Phenylalanine hydroxylase
Correct Answer: C
Rationale: An X-linked urea-cycle block causes carbamoyl phosphate to accumulate and enter pyrimidine
synthesis, raising orotic acid. Unlike a primary pyrimidine synthesis defect, it causes hyperammonemia
without megaloblastic anemia.
Question 12. An infant has severe fasting hypoglycemia, hepatomegaly, lactic acidosis,
hyperuricemia, and hyperlipidemia. Which enzyme defect is most likely?
A. Glucose-6-phosphatase deficiency
B. Lysosomal alpha-1,4-glucosidase deficiency
C. Muscle glycogen phosphorylase deficiency
D. Galactose-1-phosphate uridyltransferase excess
Correct Answer: A
Rationale: Glucose-6-phosphatase is needed for the final step of hepatic glycogenolysis and gluconeogenesis. Its
absence traps glucose-6-phosphate, promoting glycogen, lactate, uric acid, and lipid accumulation.
Question 13. An infant has neurodegeneration, an exaggerated startle response, and a cherry-red
macula without hepatosplenomegaly. Which enzyme is deficient?
A. Alpha-galactosidase A
B. Sphingomyelinase
C. Hexosaminidase A
D. Arylsulfatase A
Correct Answer: C
Rationale: Hexosaminidase A deficiency causes GM2 ganglioside accumulation in neurons. Absence of
hepatosplenomegaly helps distinguish it from sphingomyelinase deficiency.
Question 14. A young adult has tendon xanthomas, very high LDL cholesterol, and a parent with
premature coronary disease. Which molecular defect is most likely?
A. Increased hepatic LDL clearance
B. Reduced LDL receptor function
C. Absent lipoprotein lipase causing isolated chylomicrons
D. Deficient apolipoprotein A-I causing only low HDL
Correct Answer: B
Rationale: Impaired LDL receptor activity reduces hepatic removal of circulating LDL and markedly elevates
atherosclerotic risk. Tendon xanthomas and early coronary disease support this diagnosis.
COMSAE Comprehensive Examination 2026/2027 | Verified Questions
COMSAE Comprehensive Examination
2026/2027 | Verified Questions
National Board of Osteopathic Medical Examiners | COMSAE Comprehensive Examination | Professional
Osteopathic Medical Candidates
176 Verified Questions | 4 Core Domains | Academic Year 2026/2027
Prepared by
NBOME | COMSAE Comprehensive Examination
Comprehensive Licensing Examination Actual Exam | Academic Year 2026/2027
COMSAE Comprehensive Examination 2026/2027 | Verified Questions
,INTRODUCTION
This document contains exactly 176 original Medical-Level questions organized across four core domains: Domain
1, Foundational Biomedical Sciences (44); Domain 2, Osteopathic Principles and Practice (44); Domain 3, Clinical
Problem Solving and Patient Management (44); and Domain 4, Health Maintenance and Preventive Medicine (44).
The content integrates biomedical mechanisms, osteopathic diagnosis and treatment, clinical decision-making,
patient safety, and evidence-based prevention for the Comprehensive Licensing Examination aligned to Academic
Year 2026/2027.
ACTUAL QUESTIONS
Domain 1: Foundational Biomedical Sciences
Question 1. A reversible inhibitor competes with substrate for an enzyme's active site. Which
kinetic change is expected?
A. The apparent Km increases while Vmax remains unchanged.
B. The apparent Km decreases while Vmax increases.
C. Vmax decreases while Km remains unchanged.
D. Both Km and Vmax decrease to zero.
Correct Answer: A
Rationale: More substrate can overcome competitive inhibition, so the original maximal velocity remains
attainable. A higher substrate concentration is needed to reach half-maximal velocity, increasing the apparent
Km.
Question 2. A patient with metabolic acidosis has a bicarbonate concentration of 12 mEq/L and an
arterial carbon dioxide pressure of 40 mm Hg. Which interpretation is most accurate?
A. Respiratory compensation is appropriate.
B. A concurrent respiratory alkalosis is present.
C. A concurrent respiratory acidosis is present.
D. The values show isolated metabolic alkalosis.
Correct Answer: C
Rationale: Winter's relationship predicts a carbon dioxide pressure near 26 mm Hg, with a small expected
range, when bicarbonate is 12. A measured value of 40 is too high for compensation and indicates added
respiratory acidosis.
Question 3. A woman has a pathogenic mitochondrial DNA variant with high heteroplasmy. Which
inheritance pattern is expected?
A. The variant follows a strict autosomal recessive pattern.
B. All of her children may inherit the variant, but clinical severity can differ.
C. Only her sons can inherit the variant.
D. An affected father transmits the variant to every daughter.
Correct Answer: B
Rationale: Mitochondria in the embryo are derived predominantly from the oocyte, producing maternal
transmission. Heteroplasmy and replicative segregation cause variable organ involvement and severity among
offspring.
Question 4. Successive generations of a family develop a neurologic disorder at younger ages with
increasing severity. Which genetic mechanism best explains this pattern?
A. Random X chromosome inactivation alone
B. Loss of all mitochondrial DNA
C. Balanced reciprocal translocation without gene disruption
D. Expansion of a trinucleotide repeat
Correct Answer: D
Rationale: Unstable repeat expansion during gametogenesis can increase repeat length in later generations.
The larger expansion often produces earlier onset or greater severity, a pattern called anticipation.
COMSAE Comprehensive Examination 2026/2027 | Verified Questions
,Question 5. An autosomal recessive disease affects 1 in 10,000 people in a population at
equilibrium. Approximately what proportion of the population consists of carriers?
A. 1 in 5,000
B. 1 in 50
C. 1 in 100
D. 1 in 10,000
Correct Answer: B
Rationale: The affected frequency is q squared, so q is 0.01. The carrier frequency is approximately 2q when the
allele is rare, or about 0.02, which equals 1 in 50.
Question 6. A patient with severe dietary restriction has bleeding gums, perifollicular
hemorrhages, and poor wound healing. Which biochemical step is impaired?
A. Hydroxylation of proline and lysine residues in collagen
B. Oxidative deamination of dopamine
C. Gamma carboxylation of glutamate in clotting factors
D. Conversion of methylmalonyl-CoA to succinyl-CoA
Correct Answer: A
Rationale: Vitamin C is a cofactor for prolyl and lysyl hydroxylases in the endoplasmic reticulum. Impaired
hydroxylation weakens collagen triple helices and connective tissue integrity.
Question 7. A patient has macrocytic anemia, loss of vibration sense, and elevated methylmalonic
acid. Which deficiency is most likely?
A. Folate deficiency
B. Iron deficiency
C. Vitamin K deficiency
D. Vitamin B12 deficiency
Correct Answer: D
Rationale: Vitamin B12 is required for methylmalonyl-CoA metabolism and neurologic myelin maintenance.
Folate deficiency can cause megaloblastic anemia but does not raise methylmalonic acid or cause the
characteristic posterior-column findings.
Question 8. An infant has lactic acidosis and neurologic impairment due to pyruvate
dehydrogenase deficiency. Which dietary strategy can reduce reliance on the blocked pathway?
A. A diet composed only of simple glucose
B. High-dose fructose with no fat
C. A ketogenic diet rich in fat and low in carbohydrate
D. Elimination of all dietary protein and fat
Correct Answer: C
Rationale: Pyruvate cannot efficiently become acetyl-CoA, so carbohydrate use increases lactate. Ketone bodies
provide an alternative acetyl-CoA source for the brain and other tissues.
Question 9. A man develops jaundice and dark urine after receiving an oxidant medication. Blood
smear shows bite cells. Which defect is most likely?
A. Pyruvate kinase excess
B. Factor VIII deficiency
C. Hereditary elliptocytosis from collagen loss
D. Glucose-6-phosphate dehydrogenase deficiency
Correct Answer: D
Rationale: Reduced NADPH leaves erythrocytes unable to regenerate reduced glutathione during oxidative
stress. Denatured hemoglobin forms Heinz bodies that splenic macrophages remove, creating bite cells.
COMSAE Comprehensive Examination 2026/2027 | Verified Questions
, Question 10. A patient has anemia, jaundice, splenomegaly, spherocytes, and increased mean
corpuscular hemoglobin concentration. Which structural abnormality is most likely?
A. Reduced platelet glycoprotein IIb/IIIa
B. A defect in spectrin or ankyrin anchoring the red cell membrane
C. Absent beta-globin synthesis
D. Excess erythrocyte glucose-6-phosphate dehydrogenase
Correct Answer: B
Rationale: Loss of membrane surface area from cytoskeletal defects produces dense spherical erythrocytes with
poor deformability. Splenic sequestration causes extravascular hemolysis and explains why splenectomy
reduces anemia.
Question 11. A male neonate develops hyperammonemia, low blood urea nitrogen, and elevated
urinary orotic acid without megaloblastic anemia. Which enzyme is deficient?
A. Branched-chain alpha-ketoacid dehydrogenase
B. Orotate phosphoribosyltransferase
C. Ornithine transcarbamylase
D. Phenylalanine hydroxylase
Correct Answer: C
Rationale: An X-linked urea-cycle block causes carbamoyl phosphate to accumulate and enter pyrimidine
synthesis, raising orotic acid. Unlike a primary pyrimidine synthesis defect, it causes hyperammonemia
without megaloblastic anemia.
Question 12. An infant has severe fasting hypoglycemia, hepatomegaly, lactic acidosis,
hyperuricemia, and hyperlipidemia. Which enzyme defect is most likely?
A. Glucose-6-phosphatase deficiency
B. Lysosomal alpha-1,4-glucosidase deficiency
C. Muscle glycogen phosphorylase deficiency
D. Galactose-1-phosphate uridyltransferase excess
Correct Answer: A
Rationale: Glucose-6-phosphatase is needed for the final step of hepatic glycogenolysis and gluconeogenesis. Its
absence traps glucose-6-phosphate, promoting glycogen, lactate, uric acid, and lipid accumulation.
Question 13. An infant has neurodegeneration, an exaggerated startle response, and a cherry-red
macula without hepatosplenomegaly. Which enzyme is deficient?
A. Alpha-galactosidase A
B. Sphingomyelinase
C. Hexosaminidase A
D. Arylsulfatase A
Correct Answer: C
Rationale: Hexosaminidase A deficiency causes GM2 ganglioside accumulation in neurons. Absence of
hepatosplenomegaly helps distinguish it from sphingomyelinase deficiency.
Question 14. A young adult has tendon xanthomas, very high LDL cholesterol, and a parent with
premature coronary disease. Which molecular defect is most likely?
A. Increased hepatic LDL clearance
B. Reduced LDL receptor function
C. Absent lipoprotein lipase causing isolated chylomicrons
D. Deficient apolipoprotein A-I causing only low HDL
Correct Answer: B
Rationale: Impaired LDL receptor activity reduces hepatic removal of circulating LDL and markedly elevates
atherosclerotic risk. Tendon xanthomas and early coronary disease support this diagnosis.
COMSAE Comprehensive Examination 2026/2027 | Verified Questions
